The Center for Complex Generics

FDA and the Center for Research on Complex Generics (CRCG) hosted a public workshop on April 20-21, 2023: Considerations for and Alternatives to Comparative Clinical Endpoint and Pharmacodynamic Bioequivalence Studies for Generic Orally Inhaled Drug Products

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About the Event:

FDA recommendations for establishing bioequivalence (BE) with local drug delivery for orally inhaled drug products (OIDPs) often involve study designs for conducting comparative clinical endpoint (CCEP) and pharmacodynamic (PD) BE studies. Considering the difficulties that these studies can present for generic drug developers, FDA product-specific guidance (PSG) recommendations for some OIDPs have included alternative BE approaches that do not involve CCEP BE studies. However, understanding what studies may be suitable as part of an alternative BE approach can be difficult when developing generics for certain inhalation products with complex formulations, such as suspension-based metered dose inhalers (MDIs) and dry powder inhalers (DPIs).

The purpose of this two-day OIDP workshop is to discuss the current scientific and regulatory perspectives for using in vitro, in vivo, and in silico studies as alternatives to CCEP and PD BE studies, and to explore potential designs for alternative BE approaches that can address the particular challenges associated with establishing local drug delivery equivalence for suspension-based MDIs and DPIs. The workshop will begin with a reflection on the successes, limitations, and challenges with BE approaches that include CCEP and PD BE studies. Next, two parallel sessions will provide focused discussion on the in vitro, in vivo, and in silico studies that may serve as alternatives to CCEP and PD BE studies, where these interactive sessions will allow for small group discussions centered on the technical and practical aspects of these studies when used across OIDPs. The workshop will conclude with panel discussions for MDIs and DPIs that will provide participants the opportunity to discuss their study designs and issues with applying alternative BE approaches in lieu of CCEP and PD BE studies, with the goal of identifying where consensus can be achieved between collaborators from government, industry, and academia on what may constitute adequate alternative BE approaches for complex OIDPs.

Workshop Topics:

• Reviewing successes with the use of CCEP and PD BE studies to establish BE for locally acting OIDPs, and discussing relevant challenges
• Evaluating alternative BE approaches that utilize in vitro, in vivo, and in silico studies, instead of CCEP and PD BE studies, and discussing relevant technical and practical issues when used with different OIDPs
• Discussing the integration of multiple alternative in vitro, in vivo, and in silico studies to form cohesive alternative BE approaches in lieu of CCEP or PD BE studies for MDIs and DPIs

FDA and the Center for Research on Complex Generics—which is a collaboration between the University of Maryland School of Pharmacy and the University of Michigan College of Pharmacy—are dedicated to advancing programs that stimulate scientific dialogue, disseminate current insights about complex generics, and generate new knowledge in support of FDA’s mission to promote and protect the public health by increasing access to safe and effective generic medicines.

Audience:

This workshop is primarily suggested for the generic drug industry and other involved collaborators, including consultants and contract research organizations that support generic drug applications.

Workshop Recordings:

• Day 1-Symposium I: Welcome, Intro, Talks
• Day 1-Symposium I: Talks, Panel Discussion
• Day 1-Symposium II: Introduction, Plenary Talk
• Day 1-Symposium II: Session 1 Talks, Closing Remarks
• Day 1-Symposium II: Session 2 Talks
• Day 2-Symposium II: Overview, Session 1 Talks
• Day 2-Symposium II: Session 2 Talks
• Day 2-Symposium II: Session 3 Talks, Panel Discussion, Closing Remarks

Workshop Slides:

Day 1: April 20, 2023

Welcome
Anna Schwendeman, PhD, Co-Director, CRCG

Opening Remarks
Robert Lionberger, PhD, Director, ORS, OGD, CDER, FDA

Workshop Day 1 Overview
Elizabeth Bielski, MS, PhD, Senior Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

SYMPOSIUM I: Successes and Challenges Associated with the Use of Comparative Clinical Endpoint and Pharmacodynamic Bioequivalence Studies for Locally Acting Orally Inhaled Drug Products

In this symposium, FDA presenters will provide an overview on where the use of CCEP BE studies and PD BE studies have been successful for supporting locally acting generic OIDPs. This will be followed by presentations from industry on the encountered challenges with these in vivo BE studies, and potential ways for addressing them. 

Speaker Introductions
Paramjeet Kaur, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA

Challenges and General Considerations of Conducting Pharmacodynamic Equivalence Studies for Albuterol Sulfate Metered Dose Inhalers
Ke Ren, PhD, Deputy Director, DB-III, OB, OGD, CDER, FDA

Challenges and Recommendations in Comparative Clinical Endpoint Bioequivalence Studies in Dry Powder Inhaler Products
Stephanie Soukup, MD, Physician, DCR, OSCE, OGD, CDER, FDA

Considerations for FEV1-based Comparative Clinical Endpoint or Pharmacodynamic Bioequivalence Studies for Orally Inhaled Drug Products
Yuqing Gong, PhD, Pharmacologist, DQMM, ORS, OGD, CDER, FDA

Implementing a Clinical Endpoint BE Study for Wixela Inhub: An Industry Viewpoint
Jonathan Ward, BA (Hons), PhD, VP & Head of Global Clinical, Respiratory, Viatris

Q&A Session with Panel

• Moderator: Michael Spagnola, MD, Lead Physician, OCSE, OGD, CDER, FDA
• Panelists:
  Yuqing Gong, PhD, Pharmacologist, DQMM, ORS, OGD, CDER, FDA
  Ke Ren, PhD, Deputy Director, DB-III, OB, OGD, CDER, FDA
  Stephanie Soukup, MD, Physician, DCR, OSCE, OGD, CDER, FDA
  Jonathan Ward, BA (Hons), PhD, VP & Head of Global Clinical, Respiratory, Viatris

SYMPOSIUM II: Integration of Alternative In Vitro, In Vivo, and In Silico Studies to Establish Bioequivalence of Locally Acting Orally Inhaled Drug Products in Lieu of Comparative Clinical Endpoint and Pharmacodynamic Bioequivalence Studies

This symposium will be comprised of three sessions that facilitate in-depth discussions on the various alternative in vitro, in vivo, and in silico studies that may be used for alternative BE approaches in lieu of CCEP and PD BE studies for locally acting OIDPs. These sessions will cover the scientific and technical challenges of these approaches along with the potential ways they may be used together for more complex OIDPs. Sessions 1 and 2 will run in parallel followed by Session 3.

Speaker Introduction
Elizabeth Bielski, MS, PhD, Senior Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Plenary Talk: Designing Alternatives to Comparative Clinical Endpoint and Pharmacodynamic Bioequivalence Studies – Does One Approach Fit All for Generic Orally Inhaled Drug Products?
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

SESSION 1: In Vitro Studies that May Contribute to Alternative Bioequivalence Approaches for Locally Acting Orally Inhaled Drug Products

This session will run in parallel with Session 2 and will cover vaalterrious in vitro alternative studies, including dissolution studies, realistic aerodynamic particle size distribution (APSD), particle morphology and other advanced characterization methods. The scientific and practical challenges with using these approaches for different OIDPs will be discussed.

Speaker Introduction Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Considerations and Challenges for Dissolution Testing of Orally Inhaled Drug Products (OIDPs)
Elizabeth Bielski, MS, PhD, Senior Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Dissolution Tests for OIDPs: Opportunities and Challenges
Guenther Hochhaus, PhD, Professor, Pharmaceutics, College of Pharmacy, University of Florida

Considerations for Conducting More Realistic Aerodynamic Particle Size Distribution Testing for Orally Inhaled Drug Products
Susan Boc, PhD, Pharmacokineticist, DTP-I, ORS, OGD, CDER, FDA

Which Test and Handling Factors Affect the MDI Performance?
Mårten Svensson, PhD, CEO, Emmace Consulting AB

Plenary Closing Remarks for Virtual Attendees on Day 1
Markham Luke, MD, PhD, FAAD, Director, DTP-I, ORS, OGD, CDER, FDA

Small Group Discussions – Dissolution (in person only) Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Sub-Session Summary – Dissolution (in person only) Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Small Group Discussions – Realistic APSD (in person only) Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Sub-Session Summary – Realistic APSD (in person only) Session 1
Nicholas Holtgrewe, PhD Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

SESSION 2: In Vivo and In Silico Studies that May Contribute to Alternative Bioequivalence Approaches for Locally Acting Orally Inhaled Drug Products

This session will run in parallel with Session 1 and will introduce various in vivo and in silico alternative studies, including alternative pharmacokinetic (PK) studies. The challenges with proper study design, model selection, purpose and validation will be discussed.

Speaker Introduction Session 2
Rukia Mchumo, PhD Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Total and Regional Lung Delivery of Salbutamol in Subjects with Idiopathic Pulmonary Fibrosis (IPF)
Omar S. Usmani, MBBS, PhD, FHEA, FRCP, FERS, Professor, Respiratory Medicine & Consultant Physician, National Heart, Lung Institute, Imperial College London, Royal Brompton Hospital, St. Mary’s

Biopharmaceutical Characterization of Orally Inhaled Drug Products Using Scintigraphy in Combination with Charcoal Block - Case Study Ciprofloxacin Dry Powder for Inhalation
Heino Stass, PhD, Senior Clinical Pharmacology Consultant, Bayer AG

Model Purpose and Selection for Supporting Development and Approval of Generic Locally-Acting Orally Inhaled Drug Products in the United States
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Determining the Role of In Silico Methods for OINDP Generic Biowaivers
William Ganley, MChem, PhD, Head of Computational Pharmaceutics, Nanopharm Ltd. 

Plenary Closing Remarks for Virtual Attendees on Day 1
Markham Luke, MD, PhD, Director, DTP I, ORS, OGD, CDER, FDA

Small Group Discussions – Alternative PK Studies (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Sub-Session Summary – Alternative PK Studies (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Small Group Discussions – Model Selection and Model Purpose (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Sub-Session Summary – Model Selection and Model Purpose (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Day 2: April 21, 2023

Workshop Day 2 Overview
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

SESSION 1 (continued): In Vitro Studies that May Contribute to Alternative Bioequivalence Approaches for Locally Acting Orally Inhaled Drug Products 

Speaker Introduction Session I
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Alternative Bioequivalence Approach Using Morphologically-Directed Raman Spectroscopy (MDRS) on Nasal Spray Suspensions
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA

Understanding Time-Evolved Changed in Morphology of Pharmaceutical Aerosol Systems
Jag Shur, PhD, Vice President ‑ Science and Technology, Nanopharm Ltd. 

Laser and Optical Diagnostics for Characterization of DPIs
Agisilaos Kourmatzis, PhD, CEng, Associate Professor, School of Aerospace, Mechanical and Mechatronic
Engineering, The University of Sydney 

The Use of In Vitro Characterization Techniques to Support the Demonstration of Bioequivalence of Generic Orally Inhaled Products Designed to Be Bioequivalent to Their Reference Listed Drugs
Xian-Ming Zeng, MSc, PhD, CEO, Transpire Bio Inc.
No slides available

Small Group Discussions – Morphology (in person only), Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA  

Sub-Session Summary – Morphology (in person only) Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Small Group Discussions – Other In Vitro Techniques (in person only), Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Sub-Session Summary – Other In Vitro Techniques (in person only) Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

SESSION 2 (continued): In Vivo and In Silico Studies that May Contribute to Alternative Bioequivalence Approaches for Locally Acting Orally Inhaled Drug Products

Speaker Introduction Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Acceptability of Using Alternative PK Metrics from Systemic Pharmacokinetic (PK) Data of Generic OIDPs via Population PK
Kairui (Kevin) Feng, PhD, Reviewer, DQMM, ORS, OGD, CDER, FDA

Feasibility of Predicting Regional Lung Exposure from Systemic Pharmacokinetic (PK) Data of Generic OIDPs via Population PK
Jürgen Bulitta, PhD, Professor, Department of Pharmacotherapy and Translational Research,
College of Pharmacy, University of Florida 

Patient-Specific Aerosol Deposition Assessment – Technology and Validation
Jan De Backer, PhD, CEO, Fluidda Inc. 

Cluster-Informed In Silico and In Vivo Regional Deposition Assessments
Ching-Long Lin, PhD, Edward M. Mielnik and Samuel R. Harding Professor and Department Executive Officer, Department of Mechanical Engineering, University of Iowa

Small Group Discussions – PK Metrics to Inform Regional Deposition (in person only), Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Sub-Session Summary – PK Metrics to Inform Regional Deposition (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Small Group Discussions – Regional Deposition Prediction Validation (in person only), Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Sub-Session Summary – Regional Deposition Prediction Validation (in person only) Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

SESSION 3: Holistic Alternative Bioequivalence Approaches in Lieu of Comparative Clinical Endpoint and Pharmacodynamic Bioequivalence Studies for Metered Dose Inhalers and Dry Powder Inhalers

This session will provide an opportunity for participants to hear discussion summaries from Sessions 1 and 2 along with in-depth panel discussions on where alternative BE approaches may be possible for MDIs and DPIs with complex formulations. Session summary presentations will be presented by FDA, while the panel discussions will include representatives from FDA, academia, and industry.

Speaker Introductions
Ping Du, PhD, Reviewer, OB, DB-II, OGD, CDER, FDA

Summary of Session 1
Nicholas Holtgrewe, PhD, Chemist, DCDA, OTR, OPQ, CDER, FDA
Bryan Newman, PhD, Lead Pharmacologist, DTP-I, ORS, OGD, CDER, FDA

Summary of Session 2
Rukia Mchumo, PhD, Pharmacologist, DB-II, OB, OGD, CDER, FDA
Ross Walenga, PhD, Chemical Engineer, DQMM, ORS, OGD, CDER, FDA

Q&A Session with Panel on MDIs

• Moderator: Diana Vivian, PhD, Associate Director, DB-II, OB, OGD, CDER, FDA  
• Panelists:
  Per Bäckman, PhD, Senior Adviser - Inhalation Science, Per Backman/Emmace Consulting AB
  William Ganley, MChem, PhD, Head of Computational Pharmaceutics, Nanopharm Ltd.
  Mark Lepore, MD, Chief Medical Officer, Transpire Bio
  Markham Luke, MD, PhD, FAAD, Director, DTP-I, ORS, OGD, CDER, FDA
  Qing Liu, PhD, Deputy Director, OB, OGD, CDER, FDA
  Gur Jai Pal Singh, PhD, Senior Vice President, Cipla Respiratory Center of Excellence
  Yu Chung Tsang, BSc, PhM, PhD, Chief Scientific Office, Biopharmaceutics & Biostatistics, Global Regulatory Affairs, Apotex Inc.
  Liang Zhao, PhD, Director, DQMM, ORS, OGD, CDER, FDA

Q&A Session with Panel on DPIs

• Moderator: Darby Kozak, PhD, Deputy Director, DTP-I, ORS, OGD, CDER, FDA  
• Panelists:
  William Ganley, MChem, PhD, Head of Computational Pharmaceutics, Nanopharm Ltd.  
  Abhishek Gupta, PhD, PMP, Chief Scientific Officer and Interim Chief Corporate Dev Officer, Transpire Bio
  Mark Banaszak Holl, PhD, Professor and Associate Dean, Mechanical and Materials Engineering, Division of Pulmonology, Allergy, and Critical Care Medicine, University of Alabama at Birmingham
  Markham Luke, MD, PhD, FAAD, Director, DTP-I, ORS, OGD, CDER, FDA  
  Gur Jai Pal Singh, PhD, Senior Vice President, Cipla Respiratory Center of Excellence  
  Diana Vivian, PhD, Associate Director, DB-II, OB, OGD, CDER, FDA  
  Xian-Ming Zeng, MSc, PhD, CEO, Transpire Bio  
  Liang Zhao, PhD, Director, DQMM, ORS, OGD, CDER, FDA  

Closing Remarks
Bing Li, PhD, Associate Director for Science, OB, OGD, CDER, FDA 

For More Information: If you have any questions about this workshop please contact info@complexgenerics.org.