Evolving Regulatory Science for Generic Drugs

Transcription

1 Evolving Regulatory Science for Generic Drugs Wenlei Jiang, Ph.D. Senior Science Advisor Office of Research and Standards Office of Generic Drug Center for Drug Evaluation and Research Food and Drug Administration Jul 13th, 2017 American Society for Quality Section 509 Biomed/Biotech SIG, Rockville, MD Disclaimer: The views expressed in this presentation are those of the speaker and not necessarily those of the Food and Drug Administration (FDA).

2 Generic Drugs Generic drugs are copies of reference listed drug (RLD) Same in active ingredient, dosage form, safety, strength, routes of administration. 2

3 New Drug Application (NDA) vs. Abbreviated New Drug Application (ANDA) NDA 1. Chemistry 2. Manufacturing 3. Testing 4. Labeling 5. Inspection 6. Animal Studies 7. Clinical Studies 8. Bioavailability ANDA 1. Chemistry 2. Manufacturing 3. Testing 4. Labeling 5. Inspection 6. Bioequivalence 3

4 Bioequivalence The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administrated at the same molar dose under similar conditions in an appropriately designed study (21 CFR 320.1) 4

5 Approaches to Determining Bioequivalence (21 CFR320.24) In vivo measurement of active moiety or moieties in biologic fluid PK study In vivo pharmacodynamic comparison PD study In vivo limited clinical comparison Bioequivalence study with clinical endpoints In vitro comparison Any other approach deemed appropriate by FDA 5

6 Bioequivalence Study Design and Criteria Study design: Single dose 2 way crossover Sequence 1 T washout period R C max No better No worse ln Concentration AUC Time Sequence 2 R washout period T T= Test Drug R= Reference Listed Drug (RLD) 100 T max - time of maximum concentration Time % confidence interval for the ratio of test/reference within % 6

7 Possible Outcome of BE Studies Demonstrate BE Fail to Demonstrate BIE Fail to Demonstrate BE Demonstrate BIE Demonstrate BIE 80% T/R (%) 125% 7

8 Limited Access of Complex Generic Drugs Orally inhaled drug products PLGA microspheres No Generics No Generics Ophthalmic products with generics available < 50% Doxil shortage Topical drug products with generics available < 40% A $2,500 tube of cold-sore cream? Now that stings by David Lazarus in the Los Angeles Times, March 5, 2015 ( 8

9 Questions about Generic Drug Review Standards One size does not fit all e.g., narrow therapeutic index drugs Cmax and AUC are insufficient for certain drugs Can bioequivalence conclusion be extrapolated from healthy subject to patients? 9

10 Anecdotes and Controversies on Generic Drugs Physician surveys, case reports, and "switchback" rates from large-scale generic conversions imply that all generic formulations may not be equal to the brand drug for all patient groups. Where are the savings? 2007 position statement the society opposes formulation substitution of antiepileptic drugs for the treatment of epilepsy without physician and patient approval Reduced drug cost but Increased monitoring cost 10

11 Regulatory Science Needs for Generic Drugs Develop innovative equivalence approaches for complex drug products Set appropriate generic drug review standards Investigate questions of product substitutability Approve safe, effective, affordable generic drugs based on the best currently available science 11

12 GDUFA Regulatory Science The FDA committed to employ regulatory science initiatives for generic drugs based on 2012 GDUFA. Office of Research and Standards (ORS) established in Lead the implementation of the regulatory science commitments - Translate research results into standards Contracts/Grants ($$) and ORISE New Contracts/Grants Cumulative Funds Under Management Cumulative External Projects Under Management FY2016 $20 M 16 $75M 85 FY2015 $26.8M 25 $72M 95 FY2014 $22.8M 35 $54M 76 FY2013 $20.9M 29 $31M 41 FY2012 $3.6M 4 15 FY2011 $2.2M 3 12 FY2010 $3.1M

13 Develop Innovative Equivalence Approaches for Complex Drug Products

14 Complex Drug Products Complex active ingredients (e.g., peptides, polymeric compounds, complex mixtures of APIs, naturally sourced ingredients); Complex formulations/dosage forms (e.g., liposomes, colloids, transdermal, longacting injectables); Complex routes of delivery (e.g., locally acting drugs such as dermatological products and complex ophthalmological products and otic dosage forms that are formulated as suspensions, emulsions or gels) Complex drug-device combination products (e.g., auto injectors, nasal spray, metered dose inhalers) Other products where complexity or uncertainty concerning the approval pathway or possible alternative approach would benefit from early scientific engagement. GDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROGRAM. 14

15 Continuing Research on Complex Top 10 areas Drug Products Complex Active Ingredients Topical Dermatological Products Inhalation Products Ophthalmic Products Nasal Products Liposomes and Nanomaterials Microspheres (Long acting injectables) Complex Drug-Device Combinations Abuse Deterrent Formulations Transdermal Delivery Systems FY 2018 Generic Drug Research Public Workshop, May 3 rd,

16 Doxorubicin HCl Liposomes Proprietary Name: Doxil Generic Name: Doxorubicin HCl liposome injection Indication and regimen: Aids-related Kaposi s Sarcoma Ovarian cancer Multiple myeloma with bortezomib Mechanism of Action Passively targets tumor sites due to its small size and persistence in the circulation (EPR effect) Free doxorubicin HCl becomes available at the tumor cell. The exact mechanism of release is not understood. Doxorubicin HCl binds DNA and inhibits nucleic acid synthesis. 16

17 Challenges in Demonstrating Therapeutic Equivalence of Parenteral Nano Drug Products Pharmaceutical Equivalence + Bioequivalence = Therapeutic Equivalence Qualitative (Q1)/Quantitative (Q2) sameness cannot ensure supramolecular structure sameness Conventional plasma pharmacokinetics may not fully reflect rate and extent of drug available at target sites Total drug alone insufficient to demonstrate bioequivalence 17

18 Draft Guidance on Doxorubicin Hydrochloride 18

19 Same Formulation Composition Qualitative Sameness (Q1) - Same active and inactive ingredients - Complex lipid excipients from the same origin Quantitative Sameness (Q2) - Within ±5% of an approved ingredient, but cannot exceed the highest amount within inactive ingredient database 19

20 Drug loading mechansim Same Liposome Manufacturing Process Manufacturing steps Liposome formation Extrusion Dilfiltration Incubation with drug solution Active loading of doxorubicin into the intraliposome aqueous phase by ammonium sulfate gradient Dilution, sterile filtration, aseptic filling and packaging 20

21 Equivalent In Vitro Liposome Characteristics Characteristics Lipid composition (e.g., lipid quantities, free and encapsulated drug, internal and total sulfate conc., histidine and sucrose conc., drug to lipid ratio) State of encapsulated drug Internal environment (e.g., ph, volume) Liposome morphology & number of lamella Lipid bilayer phase transition Liposome size distribution Grafted PEG at the liposome surface Surface charge In vitro drug leakage Analytical methods HPLC Cryo TEM, XRD NMR, ESR, and others TEM, Cryo-TEM, AFM DSC DLS, EM NMR Zeta potential measurement Multiple release conditions 21

22 Equivalent In vivo Plasma Pharmacokinetics of Free and Liposome Encapsulated Drug 22

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24 US Generic Parenteral Nano Drug Landscape Generic parenteral nano drug product approved sodium ferric gluconate injection (1 st generic approved in 2011) doxorubincin HCl liposome injection (1 st generic approved in 2013, 2 nd in 2017) FDA product-specific equivalence guidance developed doxorubicin HCl liposome injection (2010) verteporfin liposome injection amphotericin B liposome injection daunorubicin liposome injection sodium ferric gluconate injection ferumoxytol injection iron sucrose injection cyclosporine emulsion lanreotide acetate injection paclitaxel albumin-bound particles for injectable suspension 24

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26 Topical Drug Products Multiple dosage forms Creams, emulsions, foams, gels, lotions, ointments, aerosols. Bioequivalence challenges Locally acting on skins and their skin site action may not correlate well with systemic drug concentration Bioequivalence approaches bioequivalence study with clinical endpoint bioequivalence study with pharmacodynamics endpoint in-vivo dermatopharmacokinetic study bioequivalence study with in-vitro endpoint waiver from bioequivalence study 26

27 Bioequivalence Approaches for Topical Dermatological Products Clinical Endpoint Options Costly Time consuming Placebo effects Compliance issues Heterogeneity & severity of disease state Not the most accurate, sensitive or reproducible Dermal PK Options Challenging to measure rate & extent at site of action In vivo microdialysis In vivo skin stripping In Vitro In Vitro Skin Permeation Test (IVPT) In Vitro Drug Release Test (IVRT) Qualitatively (Q1) & Quantitatively (Q2)Physico-chemical characterization (Q3) Q3 Characterization Drug Particle Size Distribution Drug Polymorphic State Drug Amount in Aqueous Phase of the Drug Product Drug Amounts in Dissolved/Undissolved State in Drug Product Drug Product Arrangement of Matter (globules/lamella/phase states) Drug Product ph, Density, Rheology, Water Activity, Drying Rate Etc. 27

28 Open Flow Microperfusion to Evaluate Topical BE Tiffner KL et al. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clinical Pharmacokinetics (2016) First Online: 18 August

29 Set Appropriate Generic Drug Review Standards

30 Narrow Therapeutic Index Drugs General characteristics Little separation between therapeutic and toxic doses (or associated blood/plasma concentrations) Sub-therapeutic concentration may lead to serious therapeutic failure Drugs are subject to therapeutic monitoring based on pharmacokinetic (PK) or pharmacodynamic (PD) measures Drugs possess low-to-moderate (i.e., no more than 30%) within-subject variability Example Warfarin Tacrolimus Carbamazepine Phenytoin Valproic acid In clinical practice, doses are often adjusted in very small increments (less than 20%) 30

31 One Size Fits All? 31

32 Novel Bioequivalence Approach for NTI Drugs Study design: Fully replicated TRTR RTRT Acceptance criteria: Bioequivalence limits scaled based on within-subject variability of the reference listed drug (RLD) S WR BE limits Variability comparison >

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34 CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 97 NUMBER 3 MARCH

35 Long-acting Polymeric Drug Brand Route Dosing freq Risperidone Octreotide Risperdal Consta Sandostatin LAR depot Microspheres Indication IM 2 weeks Schizophrenia IM 1 month Acromegaly Naltrexone Vivitrol IM 1 month Alcohol dependence Leuprolide Lupron Depot IM 1, 3, 4, 6 months Triptorelin Trelstar IM 1, 3, 6 months Prostate cancer Prostate cancer Exendatide Bydureon SC 1 week Type 2 diabetes Goserelin Zoladex IM 1, 3 months Leuprolide acetate Eligard SC 1, 3, 4, 6 months Prostate cancer Prostate cancer 35

36 Long-acting polymeric microspheres Complexity Complex formulation and polymer inactive ingredients Complex manufacturing process Scale up challenges Lack of standard in vitro drug release assay Bioequivalence approach Formulation Q1 and Q2 the same Pharmacokinetic study Equivalence challenges Formulation sameness Demonstrate Q1 and Q2 sameness of the polymeric excipients Bioequivalence Studies Long duration Conventional BE matrix may not be sufficient to capture multiphasic in vivo release 36

37 PK Modeling to Support BE Metrics Selections for PLGA Microspheres Vivitrol Naltrexone PLGA (75:25) micropheres Indicated for alcohol dependence Every 4 weeks or once a month via IM Therapeutic plasma concentration: >1 ng/ml PopPK model developed by Alkermes Current BE recommendation Type of study: In vivo single-dose fasting Design: Parallel Strength: 380 mg/vial (dose: 380 mg) Subjects: Healthy BE Metrics: Cmax, AUC1-10, AUC10-28, and AUC0- ) Babiskin, A, et al. Pharmacokinetic modeling and simulation of naltrexone for extended-release injectable suspension to derive alternative BE metrics ACoP, 37

38 Investigate Questions of Product Substitutability

39 Brand to Generic and Generic to Generic Switching Studies in Patients Brand and Generic Lamotrigine (IR Tablet) Contract Award Protocol Approval Patient Dosed Patient Dosed Completed Whether bioequivalence (BE) in healthy subjects predict BE in epilepsy patients? Generic and Generic Lamotrigine (IR Tablet) Contract Award Protocol Developed Patient Dosed Patient Dosed Completed Whether two generics bioequivalent in epilepsy patients? Brand and Generic Tacrolimus (IR capsule) Contract Award Protocol Developed Patient dosed Completed Can the conclusion be extrapolated to other therapeutic class? 39

40 Brand vs Generic lamotrigine Bioequivalence in Epilepsy Patients (BEEP Study) Study Design Primary Outcome Drug over-encapsulated Patient Demographics Bioequivalence in Patients Generic to Brand GMR(CI) Generic Brittle Patients AUC 99.4% ( %) Cmax 101.6% ( %) Secondary Outcome Secondary analysis of seizure control and dose-related adverse events support BE 40

41 Clearly, this well designed study represents a major step forward in addressing the epilepsy community s concerns and provides valuable insight regarding AED PK variability. While encouraging, these observations do require confirmation in other patient populations. This issue of individual outliers certainly merits further study. Final data analysis from the EQUIGEN study group (EQUIvalence among GENeric AEDs) is near completion and should help further clarify this issue.

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43 The Impact The AES acknowledges that drug formulation substitution with FDA-approved generic products usually reduces cost, and does not compromise efficacy. The AES supports ongoing research by the FDA to study factors (e.g., extended-release products, tablet or capsule color and shape, nocebo effect) related to the generic substitution of AEDs in adults and children. When dispensing medications to patients, healthcare professionals should ensure that a bioequivalent FDAapproved generic product is substituted for the brand or another generic AED. For example, an immediaterelease generic product should not be dispensed as a substitute for a delayed-release or an extended-release product

44 Brand vs Generic vs Generic Tacrolimus: Multiple Dose Study in Transplant Patients Kidney Liver Bioequivalence demonstrated based on tighter BE limits for NTI drugs All formulations safely tolerated in all subjects No changes in organ functions 44

45 Substantial Increase about Patient Preference about Generic Drugs 2014 Survey (Kesseheim et al.) Over 80% Patients preferred generics over the brand Non-Caucasians - prefer brand over generic - More skeptical of generic drug clinical equivalence 2007 Survey (Shrank et al.) Less than 40% 45

46 Greater Physician Confidence about Generic Drug Safety and Efficacy Prevalence and predictors of generic drug skepticism among physicians: Results of a National Survey 2014 Survey (Kesselheim et al.) 89% believes generic are as effective as the RLD Kesselheim et al. JAMA Internal Medicine 2016;176(6): Perceptions Generics are as effective as their corresponding brand-name versions Generics are as safe as their corresponding brand-name versions Do not cause more adverse effects than their corresponding brand-name versions Respondents who strongly or somewhat agree, proportion (%(95% CI)) 89 (86-91) 91 (89-93) 73 (70-76) Further work - Limiting interactions with pharmaceutical marketing - Directed educational outreach Physician perceptions about efficacy of generic drugs 2009 Survey (Shrank et al.) Over 23% expressed negative perceptions 46

47 Summary Unique regulatory science needs for generic drug development and review Significant advancements in - Developing innovative equivalence approaches for complex drug products - Setting appropriate generic drug review standards - Investigating questions of product substitutability The science of equivalence is evolving - Advanced analytics - Modeling and simulation - Novel Pharmacokinetics FDA is committed to ensure the best science available to evaluate and approve safe, effective, and affordable generic drugs 47

48 Acknowledgement FDA Robert Lionberger Lawrence Yu Xinyuan Zhang Nan Zheng Fairouz Makhlouf Donald Schiurman Sarah Dutcher Andrew Babiskin Sam Raney Stephanie Choi University of Cincinnati University of Rochester University of Maryland Brigham Women s Hospital Medical University of Graz, Austria 48

49 Thank you! Any Question? GDUFA Regulatory Science Product Specific Guidance for Generic Drug Development ucm htm