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Totality of Evidence & Theraputic Equivalence 15 October 2016

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Put R back in R&D & recognize It is a “complex” product and process!
Invest smartly in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration
Get to know the RLD – multiple lots; open the door with large sample size
Build capability to justify measured RLD variability is relevant to development of the proposed generic/biosimilar
Exquisite regulatory communication strategy
This is not a ‘complicated process’ for which typical “good practices” will work seamlessly (e.g., typical project management approach); this is a complex process – with multiple interactions and “emergent properties”
Treat it as it is - a complex process and plan; anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications

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Totality of Evidence & Theraputic Equivalence 15 October 2016

  1. 1. TotalityofEvidence&Therapeutic Equivalence:LessonsfromaCaseStudyof BioequivalenceEvaluationofaLocallyActing NasalSpray Ajaz S. Hussain, Ph.D. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 1 National Seminar, Controlled Release Society, India Chapter SciTech Centre, Mumbai (West) 15th October 2016 CLINICAL APPROACH FOR DRUG DELIVERY SYSTEMS ADHERENCETO REGULATORY REQUIREMENTS
  2. 2. PresentationOutline Answers: To questions Questions: We should ask • Why risk of development failure? • How to reduce complexity & uncertainty? • What steps mitigate risk and create competitive advantage? Challenges: Efficient Development • Complexity & uncertainty • Confidence for the patients we serve • Efficiency of development and regulatory review Background: Therapeutic Equivalence • Complex Generics; US FDA Classification & Totality of Evidence • Case example: Generic Nasal Spray • Summary of the FDA’s review chronical 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 2
  3. 3. ComplexGenerics: USFDAClassification pointsto wherethe “complexity” lies 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 3 Complex Active Ingredients LMWH, peptides, complex mixtures,.. Complex Formulations Complex Route of Delivery Complex Drug-Device Combinations Liposomes, iron colloids, nanomaterials, emulsions Locally acting drug products DPI, MDI, nasal spray, transdermal system Complex Drug Release Profile Modified release drug products (some)
  4. 4. Generic enoxaparin (USA); Biosimilar (EU)  Moreover, this approval presents a major development in the review and approval of complex drug products in the FDA that may have implications for regulatory assessments in other jurisdictions (Box 1). It further illustrates that progress in the analytical characterization of macromolecules, as well as in product and process understanding, permit demonstration of sameness for some complex drug molecule(s) coupled with adequate assessment of the immunogenicity risk. As a result of these scientific advancements and increased knowledge, unnecessary in vivo testing in animals and humans can be eliminated. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 4 All of these [EMA, ISTH, & SASAT] three guidelines advocate and rely primarily on clinical studies to establish comparability of clinical effectiveness and safety of biosimilar and innovator LMWHs. Box 1 Other regulatory guidelines on LMWHs
  5. 5. Totality of Evidence: Anemergingstandard inneed forclarity& consistency 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 5
  6. 6. SelectedCaseStudy  Draft Guidance on Mometasone Furoate Monohydrate (US FDA; September 2015)  FDA/CDER/SBIA/Chronicle: FDA Embraces Emerging Technology for Bioequivalence Evaluation of Locally Acting Nasal Sprays (19 May 2016)  FDA Disclaimer:This communication is consistent with 21CFR10.85(k) and constitutes an informal communication that represents our best judgment at this time but does not constitute an advisory opinion, does not necessarily represent the formal position of the FDA, and does not bind or otherwise obligate or commit the agency to the views expressed 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 6
  7. 7. DraftGuidanceon MometasoneFuroate Monohydrate DOSAGEFORM:Metered, spray;nasal USFDA,September2015  The generic product formulation is recommended to be qualitatively (Q1) and quantitatively (Q2) the same as the RLD product.  The generic product is recommended to deliver the same number of doses as the RLD product, and the device should be similar in shape, size, and external operating principles to ensure substitutability with the RLD product without additional need to retrain patients upon use of the generic product. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 7
  8. 8. Weight of Evidence or Totality of Evidence  In vitro, pharmacokinetic, and pharmacodynamic or clinical endpoint studies  Collectively provide sufficient information to conclude equivalence in systemic exposure and local drug delivery between two products  Equivalence assessment in vivo provides information about safety of the test product 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 8
  9. 9. The weight-of- evidenceapproach 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 9 The AAPS Journal, Vol. 15, No. 3, July 2013 Locally Acting Nasal Spray and Nasal Aerosol Products
  10. 10. EvidenceArchitecture 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 10  Integrative thinking and execution
  11. 11. FDA/CDER/SBIA/ Chronicle InterviewwithDr.BingLi, ActingDirector,Officeof GenericDrugs,Divisionof BioequivalenceI How long did it take for FDA to approve the ANDA for Mometasone Furoate nasal spray? • This application was submitted in December 2008 and was approved in March 2016 - about 8 years of work! • The application history included a refuse-to-receive determination, a dispute resolution, and a significant number of amendments…a long way to reach its approval! • Nevertheless, this approval is a great example of commitment and collaboration between CDER staff and industry to overcome challenges and embrace new technology in bringing a generic product to the American public. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 11
  12. 12. FDA/CDER/SBIA/ Chronicle InterviewwithDr.BingLi, ActingDirector,Officeof GenericDrugs,Divisionof BioequivalenceI What makes this generic approval so special? • The first generic mometasone nasal spray made available in the US market • The review was extremely complicated and involved many amendments, many internal and external meetings, and a formal dispute resolution • The review of this application involved a coordinated and collaborative effort of disciplines within OGD, the Office of Pharmaceutical Quality, and the Office of New Drugs. • This was a very timely approval – during allergy season. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 12
  13. 13. FDA/CDER/SBIA/ Chronicle InterviewwithDr.BingLi, ActingDirector,Officeof GenericDrugs,Divisionof BioequivalenceI What were some of the specific challenges encountered along the way? • The clinical endpoint BE study was unacceptable to FDA because it used API manufactured from a site that was not intended for the manufacture of the commercial batch.The two API batches showed a certain level of difference in terms of their particle size distribution. • The PK endpoint BE studies were challenging, as they always are with locally acting drugs. As I mentioned earlier, locally acting drugs lead to a low systemic drug concentrations in the blood and therefore require a sensitive analytical method.The PK endpoint BE study is one of the elements of the weight-of- evidence approach and demonstrates the comparative systemic exposure of the drug. It is considered a critical element for the overall BE evaluation 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 13
  14. 14. FDA/CDER/SBIA/ Chronicle InterviewwithDr.BingLi, ActingDirector,Officeof GenericDrugs,Divisionof BioequivalenceI What were some of the specific challenges encountered along the way? • In vitro BE studies were also challenging and were repeated multiple times.There are a total of six in vitro BE tests recommended for this drug product.The firm first conducted all six tests using API manufactured by a single site. As the firm later switched to API manufactured by a second site (for batches intended for commercial use), they had to repeat some of these in vitro studies. • The generic used an [anhydrous] API, whereas the innovator used a monohydrate API. [Anhydrous] and monohydrate drug substance have different hydration levels.Typically, a generic firm uses the same form as that of RLD. In this case, XYZ chose to use a different form. Since the [anhydrous] form of the API and the monohydrate form may undergo inter-conversion, we required adequate evidence to demonstrate that the final drug formulation remain [anhydrous] throughout the shelf life. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 14
  15. 15. FDA/CDER/SBIA/ Chronicle InterviewwithDr.BingLi, ActingDirector,Officeof GenericDrugs,Divisionof BioequivalenceI You mentioned that the use of new technology sets a precedent for change.What does this mean for future approvals of the same class? • FDA accepted the in vitro particle size data from MDRS in lieu of the clinical endpoint BE study, deemed unacceptable due to its API manufacturing site issue. This is a first in OGD history. Clinical BE determinations are expensive and time-consuming. Pharmaceutical companies face huge challenges with recruiting patients, and the results are unpredictable in many cases. Simple, accurate in vitro studies can therefore greatly enhance ANDA reviews. This application opened the possibility for in vitro appraisals of BE to be used in the review of future ANDAs submitted to the FDA. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 15
  16. 16. Morphologically DirectedRaman Spectroscopy  Separation and identification of species in a mixed system;  analysis of micron-scale particulates with chemical specificity  Raman spectroscopy  is sensitive to the unique polymorphic forms of a substance, and  can be used to identify and investigate single or specific particles to measure size and morphology and to monitor long-term stability of a product 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 16
  17. 17. PresentationOutline Answers: To questions Questions: We should ask • Why risk of development failure? • How to reduce complexity & uncertainty? • What steps mitigate risk and create competitive advantage? Challenges: Efficient Development • Complexity & uncertainty • Confidence for the patients we serve • Efficiency of development and regulatory review Background: Therapeutic Equivalence • Complex Generics; US FDA Classification & Totality of Evidence • Case example: Generic Nasal Spray • Summary of the FDA’s review chronical 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 17
  18. 18. Complexity & Uncertainty  FDA & much of Generic Industry is ill prepared to address the challenges posed by increasing complexity of products and manufacturing processes  The paradigm for development of complex generics and for that for review of such products must evolve and mature quickly  FDA has recently instituted changes in its organization structure and added emphasis on “One QualityVoice”; this will take time to progress, thus regulatory uncertainty will remain high for the foreseeable future 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 18
  19. 19. Confidencefor the patients we serve Focus onthe crucial humanfactor!  Confidence is a critical quality attribute  Confidence in generic drugs is built upon an optimal integration of evidence derived from formulation and process design, analytical characterization and, when necessary, in vivo assessment  Pharmaceutical Equivalence (Bioequivalence) 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 19
  20. 20. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 20 generics are for minor but not serious illnesses;… and poor people are forced to ‘settle’ for generics. What do people really think of generic medicines? A systematic review and critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:173 36 % of the patients reported negative experiences after medication substitution 89 % of pharmacists reported receiving patient complaints regarding use of generic medicine, although 64 % suggested that this was due to a nocebo effect Only 50.2 % of the surveyed pharmacists agreed that all products that were approved as generic equivalents can be considered therapeutically equivalent. Just 6 % of pharmacists considered that dry powder inhalers were interchangeable. While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains, particularly within the patient and, to a lesser extent, physician groups. Nearly half the patients stated they would refuse generic substitution when it became available if this was just to save the health authority money. Generic medicines were considered to be poor quality and treated with suspicion.
  21. 21. Efficiency of development and regulatory review 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 21 Several programs in OPQ, One Quality Voice Need for additional quality regulation to “better assure quality in an increasingly globalized industry“ . “First Generics” Public Health Priority GADUFA goal date (15 months – to shorter) GDUFA research funding prioritization Need for research; Research to policy to practice - time and effectiveness. GDUFA II negotiations a pre-ANDA process Submission quality - Multiple review cycles (on average 4)
  22. 22. PresentationOutline Answers: To questions Questions: We should ask • Why risk of development failure? • How to reduce complexity & uncertainty? • What steps mitigate risk and create competitive advantage? Challenges: Efficient Development • Complexity & uncertainty • Confidence for the patients we serve • Efficiency of development and regulatory review Background: Therapeutic Equivalence • Complex Generics; US FDA Classification & Totality of Evidence • Case example: Generic Nasal Spray • Summary of the FDA’s review chronical 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 22
  23. 23. “Pharmaceutical Equivalence” Sixblindmen&theElephant or ‘ElephantintheDark’ 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 23  Q1/Q2/Q3, ……  Today … Color, Shape,…..moving towards same mechanism of release?  We lack consensus on a set of principles to integrate across multiple, orthogonal, analytical characterization tools for physical attributes and physical performance (e.g., size, shape, charge, flow, plume, …)  This is a “billion dollar” opportunity; but only for certain companies
  24. 24. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 24 Characterization of Brand Copaxone Thorough understanding of reference listed drug (Copaxone) required. Review available scientific, patent, and regulatory literature on Copaxone. Characterization by more than 60 physicochemical, biological, and immunological methods. Multiple lots (up to 50 for some attributes) were studied over several years probing the range and diversity of the commercial lots, as well as evaluating the effects of lot aging. Demonstration of Equivalence of Glatopa and Copaxone Equivalence of starting materials and basic chemistry. Equivalence of structural signatures for polymerization, depolymerization, and purification. Equivalence of physicochemical properties. Equivalence of biological and immunological properties. Example: Equivalence considerations for Glatopa® and Copaxone® http://www.momentapharma.com/AAN-Equivalence-Glatopa-Poster-6x4-PRESS.pdf (accessed 16 September 2015)
  25. 25. 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 25 Ajaz Hussain. Reducing technical and regulatory uncertainty in biosimilar development (2014)
  26. 26. Steps to mitigate risk and create competitive advantage  Put R back in R&D & recognize It is a “complex” product and process!  Invest smartly in analytics, mathematics & statistics, and large sample sizes; and in systems/integrative thinking and data integration  Get to know the RLD – multiple lots; open the door with large sample size  Build capability to justify measured RLD variability is relevant to development of the proposed generic/biosimilar  Exquisite regulatory communication strategy  This is not a ‘complicated process’ for which typical “good practices” will work seamlessly (e.g., typical project management approach); this is a complex process – with multiple interactions and “emergent properties”  Treat it as it is - a complex process and plan; anticipate and address “emergent issues” - in technical, regulatory and legal dimensions; at a certain point be prepared for stakeholder (payers, patient groups,..) communications 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 26
  27. 27. Presentation Summary Answers: To questions Questions: We should ask • Why risk of development failure? • How to reduce complexity & uncertainty? • What steps mitigate risk and create competitive advantage? Challenges: Efficient Development • Complexity & uncertainty • Confidence for the patients we serve • Efficiency of development and regulatory review Background: Therapeutic Equivalence • Complex Generics; US FDA Classification & Totality of Evidence • Case example: Generic Nasal Spray • Summary of the FDA’s review chronical 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 27
  28. 28. Thank you!  Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and our freedom. Viktor E. Frankl  Between regulatory query and response there is Design Space. In that space is our comparability protocol… 10/16/2016 © Ajaz S. Hussain | Insight, Advice & Solutions LLC 28 will be to arrive where we started and know the place for the first time. T. S. Eliot We shall not cease from exploration, and the end of all our exploring …….

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