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FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges/gaps, and future perspective

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Abstract

The pharmaceutical industry is actively applying quantitative systems pharmacology (QSP) to make internal decisions and guide drug development. To facilitate the eventual development of a common framework for assessing the credibility of QSP models for clinical drug development, scientists from US Food and Drug Administration and the pharmaceutical industry organized a full-day virtual Scientific Exchange on July 1, 2020. An assessment form was used to ensure consistency in the evaluation process. Among the cases presented, QSP was applied to various therapeutic areas. Applications mostly focused on phase 2 dose selection. Model transparency, including details on expert knowledge and data used for model development, was identified as a major factor for robust model assessment. The case studies demonstrated some commonalities in the workflow of QSP model development, calibration, and validation but differ in the size, scope, and complexity of QSP models, in the acceptance criteria for model calibration and validation, and in the algorithms/approaches used for creating virtual patient populations. Though efforts are being made to build the credibility of QSP models and the confidence is increasing in applying QSP for internal decisions at the clinical stages of drug development, there are still many challenges facing QSP application to late stage drug development. The QSP community needs a strategic plan that includes the ability and flexibility to Adapt, to establish Common expectations for model Credibility needed to inform drug Labeling and patient care, and to AIM to achieve the goal (ACCLAIM).

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Acknowledgements

1) Case study presenters: Ted Rieger (Pfizer); Jason Chan (Eli Lilly); Iraj Hosseini (Genentech); Brian Topp (Merck); Annabelle Lemenuel (Roche); Tarek Leil (BMS); Sergio Ladevia (Takeda); Loveleena Bansal (Glaxo SmithKline (GSK); and lightning talk speakers (Mary Spilker (Pfizer); Richard Allen (Pfizer); Antoine Soubret (Roche); Lourdes Cucurull-Sanchez (GSK)

2) Case study assessment teams: Case Study 1A captain Weirong Wang (JNJ) and team members: Majid Vakilynejad (Takeda); Jared Weddell (Astellas); Tarek Leil (BMS); Case Study 1B captain Karim Azer (GMRI) and team members: Antoine Soubret (Roche); Lourdes Cucurull-Sanchez (GSK); Bradley Niesner (Sanofi); Case Study 1C captain Chris Penland (AZ) and team members: Andy Zhu (Takeda); Oleg Milberg (JNJ); Brian Schmidt (BMS); Spyros Stamatelos (Sanofi); Case Study 1D captain Abhishek Gulati (Astellas) and team members: Benjamin Ribba (Roche); Loveleena Bansal (GSK); Chris Penland (AZ); Case Study 2A captain Diana Clausznitzer (Abbvie) and team members: Lars Kuepfer (Bayer); Vikram Sinha (Merck); Eric Fernandez (Boehringer Ingelheim); Case Study 2B captain Jenny Chien (Lilly) and team members: Mary Spilker (Pfizer); Khamir Mehta (Amgen); Kapil Gadkar (Genentech); Case Study 2C captain Mary Spilker (Pfizer) and team members: Dinesh DeAlwis (Merck); Evan Wang (Lilly); Andy Stein (Novartis); Michael Block (Bayer); Case Study 2D captain Jeff Kearns (Novartis) and team members: Richard Allen (Pfizer); Iraj Hosseini (Genentech); Ramona Schmid (BI)

3) Meeting moderators: Cynthia Musante (Pfizer), Valeriu Damian (GSK)

4) 2019 Preliminary Group Discussion presenters: Chris Penland (Astra Zeneca); Tarek Leil (BMS); Kapil Gadkar (Genentech); Loveleena Bansal (Glaxo SmithKline (GSK); Nitin Mehrotra (Merck); Andrew Stein (Novartis); Susana Zaph (Sanofi); Timothy Nicholas (Pfizer); Antoine Soubret (Roche); Majid Vakilynejad (Takeda)

5) Selected participants who critically commented during the meeting or provided suggestions in the Discussion session engaging the audience: Holly Kimko (AstraZeneca); Dwaipayan Mukherjee (AbbVie); Sergio Iadevaia (Takeda); Jeff Kearns (Novartis); Andrew Stein (Novartis); Satyaprakash Nayak (Pfizer); Timothy Nicholas (Pfizer); Ruth Abram (Sanofi); Steven Chang (Immunetrics)

6) 2019 Preliminary Group Discussion moderators: Jane PF Bai (US FDA) Brian Schmidt (BMS), Kapil Gadkar (Genentech), Cynthia Musante (Pfizer),, Valeriu Damian (GSK)

7) The International Society of Pharmacometrics (ISoP) for providing a meeting room at ACoP10 for the purposes of the preliminary group discussion and also its virtual conferencing account to make the virtual meeting on July 1 successful

8) Enrico Smith of ISoP for assisting in setting the virtual meeting for several rounds of testing and dry-run and for live stream of the virtual meeting. Tarek Leil at Bristol Myers Squib (BMS) for his scientific discussion at the 2019 AAPS meeting

Author information

Authors and Affiliations

  1. Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, 20903, USA

    Jane P. F. Bai, Justin C. Earp, Rajanikanth Madabushi, Kunal Naik & Hao Zhu

  2. Quantitative Clinical Pharmacology, Bristol Myers Squibb, Princeton, New Jersey, USA

    Brian J. Schmidt

  3. Development Sciences, Genentech Inc., South San Francisco, California, 94080, USA

    Kapil G. Gadkar

  4. Denali Therapeutics, San Francisco, California, USA

    Kapil G. Gadkar

  5. GSK R&D – Upper Providence, 1250 S Collegeville Rd, Collegeville, Pennsylvania, 19426, USA

    Valeriu Damian

  6. Rosa & Co LLC, 751 Laurel St., Ste. 127, San Carlos, California, 94070, USA

    Christina Friedrich

  7. Certara, Canterbury, CT2 7FG, UK

    Piet H. van der Graaf

  8. Leiden Academic Centre for Drug Research, Leiden, 2333, CC, the Netherlands

    Piet H. van der Graaf

  9. Early Clinical Development, Pfizer Worldwide Research, Development, & Medical, 1 Portland Street, Cambridge, Massachusetts, 02139, USA

    Cynthia J. Musante

  10. Quantitative Translational Science, Takeda Pharmaceuticals International Co, 40 Landsdowne Street, Cambridge, Massachusetts, 02139, USA

    Mark Rogge

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  1. Jane P. F. Bai
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  12. Hao Zhu
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Contributions

Jane PF Bai, Brian Schmidt, and Kapil Gadkar contributed equally to drafting the manuscript. Valeriu Damian, Justin C Earp, Christina Friedrich, Piet van der Graaf, Kunal Naik, Rajanikanth Madabushi, Cynthia J Musante, Mark Rogge, and Hao Zhu commented on the manuscript.

Corresponding authors

Correspondence to Jane P. F. Bai, Brian J. Schmidt or Kapil G. Gadkar.

Additional information

Organizing Committee: The FDA-Industry Scientific Exchange took place virtually on July 1, 2020. The Organizing Committee members include Jane PF Bai, Justin Earp, Kunal Naik, Rajanikanth Madabushi and Hao Zhu from the US Food and Drug Administration and Brian Schmidt, Kapil Gadkar, Christina Friedrich, Piet van der Graaf, Mark Rogge from the industry.

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Bai, J.P.F., Schmidt, B.J., Gadkar, K.G. et al. FDA-Industry Scientific Exchange on assessing quantitative systems pharmacology models in clinical drug development: a meeting report, summary of challenges/gaps, and future perspective. AAPS J 23, 60 (2021). https://doi.org/10.1208/s12248-021-00585-x

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