Scientific publications

Journal of Clinical Oncology, November 2023

Regulatory Challenges: Is a Surrogate End Point Instead of Overall Survival Enough for Regulatory Approval of (Neo)Adjuvant Cancer Treatment? The Swissmedic Perspective

Matea Pavic, Anita Wolfer, Qiyu Li, Arunas Gircys, Stephanie Juritz, Andreas Wicki, Thomas Cerny, Ulrich-Peter Rohr

From a regulator's point of view, a market authorization can only be granted with a positive benefit-risk (BR) balance. Divergent clinical positions of the US-FDA and the European Medicines Agency (EMA) on surrogate end points initiated this commentary from a Swiss regulator's point of view. In collaboration with oncologists from the Swiss Human Medicines Expert Committee, Swissmedic presents and discusses relevant elements of our current regulatory decision making for (neo)adjuvant oncology drugs.

Annals of Internal Medicine, 17 October 2023

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020

Kerstin N Vokinger, Miquel Serra-Burriel, Camille E G Glaus, Ulrich-Peter Rohr, Thomas J Hwang, Simon Dalla Torre di Sanguinetto, Aaron S Kesselheim

Analysis of regulatory review duration and differences in submission times of first and supplementary indications approved between 2011 and 2020 in the United States, the European Union [EU] and Switzerland. With descriptive statistics to review times between the jurisdictions and across the therapeutic areas and a regression analysis to estimate the association between approval agency and review times.

 Journal of Clinical Research & Bioethics; Published: 14-Sep-2023

High Consistency between Regulatory Decisions for New Drugs between the Swiss Swissmedic, the European Medicines Agency and the United States Food and Drug Administration

Ulrich P Rohr, Anita Wolfer, Christine Haenggeli

SMC regulatory decisions on New Active Substance (NAS) drug approvals were compared with the FDA and EMA decisions, focusing the analysis on the same drugs and data sets, with particular focus on the oncology products, this over a 10-year-period between Jan 1st 2009 and Dec 31st, 2018. In summary, we were able to show that for the investigated 10-year time period the decision making between SMC, EMA and FDA was highly consistent and independent of therapeutic area with a consensus decision rate of 84% for non-Oncology products and 88% for Oncology Products.

Advances in Experimental Medicine and Biology*, August 2023
^{*book series}

The Regulation of Cell Therapy and Gene Therapy Products in Switzerland

Petra Kempná Bukovac, Michel Hauser, Daniel Lottaz, Andreas Marti, Iris Schmitt, Thomas Schochat

This chapter of the updated edition of 'Advances in Experimental Medicine and Biology' describes the regulation and its legal basis of cell and gene therapy products (CGTPs) in Switzerland.

Journal of Pharmaceutical Sciences, 29 July 2023

Performance Characteristics of Mass Spectrometry-Based Analytical Procedures for Quantitation of Nitrosamines in Pharmaceuticals: Insights from an Inter-laboratory Study

Jingyue Yang, Raghavi Kakarla, Tim Marzan, Bill Sherwin, Mark George, Justine Bennett, Jose Basutto, Yi Su, Jason Ollerenshaw, Justin Morin, Hervé Rebière, Annie-Francoise Maggio, Audrey Kermaïdic, Elodie Gervela, Charlotte Brenier, Corinne Civade, Denis Chauvey, Françoise Duperray, Uwe Wollein, Massimiliano Conti, Jan Tromp, Simon Meyer, Richard Wanko, Michael Wierer, Marie Bertrand, Jason Rodriguez, Cynthia Sommers, David Keire

Study by six international regulatory laboratories on analytical procedures for nitrosamine analysis. The interlaboratory results fill a knowledge gap on mass spectrometry-based techniques to quantify small molecule nitrosamines.

Clinical and Translational Science (CTS), 5 July 2023

A decade comparison of regulatory decision patterns for oncology products to all other non-oncology products among Swissmedic, European Medicines Agency, and US Food and Drug Administration

Ulrich-Peter Rohr, Mario Iovino, Leonie Rudofsky, Qiyu Li, Stephanie Juritz, Arunas Gircys, Oliver Wildner, Magda Bujar, Claus Bolte, Simon Dalla Torre di Sanguinetto, Anita Wolfer

Consensus of regulatory decisions on the same Marketing Authorization Application (MAA) are critical for stakeholders. In this context, regulatory decision patterns from Swissmedic, the US-FDA and the European Medicines Agency (EMA) were analyzed for hemato-oncology products (OP) and non-oncology products (NOP). High concordance in regulatory decisions was observed between agencies for OP as well as NOP.  The main clinical driver for divergent decisions for OP was nonrandomized trial design and low patient numbers.

Drug Safety, 19 June 2023

Hospitalisations Related to Adverse Drug Reactions in Switzerland in 2012-2019: Characteristics, In-Hospital Mortality, and Spontaneous Reporting Rate

Patrick E Beeler, Thomas Stammschulte, Holger Dressel

A joint study by the Universities of Lucerne and Zurich, the University Hospital Zurich and Swissmedic comprehensively analyses how many people in Switzerland were admitted to hospital due to adverse drug reactions from 2012 to 2019. Despite the legal obligation, only a small proportion of these were reported in the eight-year observation period.

Frontiers in Medicine, 18 May 2023

Collaborative training of regulators as an approach for strengthening regulatory systems in LMICs: experiences of the WHO and Swissmedic

Razieh Ostad Ali Dehaghi, Alireza Khadem Broojerdi, Lodovico Paganini, Hiiti B. Sillo

Study evaluating the suitability, impacts and challenges related to the training of regulators from Low- and Middle-Income countries (LMICs) offered by Swissmedic in collaboration with the World Health Organization (WHO).

Regulatory Toxicology and Pharmacology, May 2023

Artificial intelligence and real-world data for drug and food safety – A regulatory science perspective

Shraddha Thakkar, William Slikker Jr, Frank Yiannas, Primal Silva, Burton Blais, Kern Rei Chng, Zhichao Liu, Alok Adholeya, Francesco Pappalardo, Mônica da Luz Carvalho Soares, Patrick E Beeler, Maurice Whelan, Ruth Roberts, Jurgen Borlak, Martha Hugas, Carlos Torrecilla-Salinas, Philippe Girard, Matthew C Diamond, Didier Verloo, Binay Panda, Miquella C Rose, Joaquim Berenguer Jornet, Ayako Furuhama, Hong Fang, Ernest Kwegyir-Afful, Kasey Heintz, Kirk Arvidson, Juan Garcia Burgos, Alexander Horst, Weida Tong

The 11th annual GSRS conference (GSRS21) focused on 'Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI).' The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies.

Therapeutic Innovation & Regulatory Science, 18 April 2023

Comparative Expedited Regulatory Programs of U.S Food & Drug Administration and Project Orbis Partners

Lauren T Hotaki, Anu Shrestha, Monica P Bennett, Ivelisse L Valdes, Sso H Lee, Yinghua Wang, Dianne Spillman, Tina MacAulay, Melissa Hunt, Julie Gervais, Maral Mafi, Vincent Panetta, Yee Hoo Looi, Michael Shum, Eiman Atiek, Ricarda Meincke, Ulrich-Peter Rohr, Denize Ainbinder, Anat Boehm-Cagan, Osnat Luxenburg, Mateus Rodrigues Cerqueira, Laila Sofia Mouawad, Maria Fernanda Reis E Silva Thees, Krishna Prasad, R Angelo de Claro

Concurrent review of innovative cancer medicines under Project Orbis.
Project Orbis was initiated in May 2019 by FDA's Oncology Center of Excellence to facilitate faster patient access to innovative cancer therapies by providing a framework for concurrent submissions and review of oncology products among international partners. The project provides a framework for the concurrent submission and review of oncology products among leading international regulatory agencies.

Statistics in Biopharmaceutical Research (2023, VOL. 15, NO. 2, 444–449)

Cancer Clinical Trials beyond Pandemic: Report of an American Statistical Association Biopharmaceutical Section Open Forum Discussion

Rajeshwari Sridhara, Elizabeth Barksdale, Olga Marchenko, Qi Jiang, Yuki Ando, Erick Bloomquist, Michael Coory, Melissa Crouse, Evgeny Degtyarev, Theodor Framke, Boris Freidlin, David E. Gerber, Thomas Gwise, Filip Josephson, Lorenzo Hess, Paul Kluetz, Daniel Li, Sumithra Mandrekar, Martin Posch, Khadija Rantell, Bohdana Ratitch, AndrewRaven, Kit Roes, Kaspar Rufibach, Sinan B. Sarac, Richard Simon, Harpreet Singh, Marc Theoret, Andrew Thomson, Emmanuel Zuber, Yuan Li Shen, and Richard Pazdur

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the US FDA Oncology Center of Excellence and LUNGevity Foundation on January 14, 2021, and February 8, 2021. Diverse stakeholders including oncologists, patient advocates, experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on how best to incorporate lessons learned during the COVID-19 pandemic into the design of future oncology trials. While recognizing that decentralized or hybrid cancer trials may increase variability associated with measurement error and potentially increase bias in treatment effect estimation, panel discussions highlighted the importance of flexibility for decreasing patient burden, which has the potential to increase access to and retention in cancer clinical trials and may broaden the representation of real-world patients in the trial setting.

Statistics in Biopharmaceutical Research (2023, VOL. 15, NO. 3, 697–703)

Designing Dose-Optimization Studies in Cancer Drug Development: Discussions with Regulators

Olga Marchenko, Rajeshwari Sridhara, Qi Jiang, Elizabeth Barksdale, Yuki Ando, Dinesh De Alwis, Katie Brown, Laura Fernandes, Mark T. J. van Bussel, Qiuyi Choo, Michael Coory, Elizabeth Garrett-Mayer, Thomas Gwise, Lorenzo Hess, Rong Liu, Sumithra Mandrekar, Daniele Ouellet, José Pinheiro, Martin Posch, Nam Atiqur Rahman, Khadija Rerhou Rantell, Andrew Raven, Sarem Sarem, Suman Sen, Mirat Shah, Yuan Li Shen, Richard Simon, Marc Theoret, Ying Yuan, and Richard Pazdur

The article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forums on March 18th, June 10th, and July 8th of 2021, organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence and the LUNGevity Foundation. Diverse stakeholders including oncologists, patient advocates, experts from regulatory agencies across the world, academicians, and representatives from the pharmaceutical industry engaged in a lively discussion on strategies for and designs of dose-optimization studies in cancer drug development. Dose-optimization is one of the major challenges in oncology drug development. The discussions were focused on considerations in designing dose-optimization studies of products for treatment of cancer patients in pre-approval and post-approval stages. Presenters and panelists discussed diverse ideas and methods and agreed that a shift in paradigm is required in oncology drug development that should improve dose optimization while not unnecessarily delaying patient access to potentially efficacious new treatments.

Statistics in Biopharmaceutical Research (2023, VOL. 15, NO. 2, 450–456)

Evaluation of Treatment Effect in Underrepresented Population in Cancer Trials: Discussion with International Regulators

Rajeshwari Sridhara, Olga Marchenko, Qi Jiang, Elizabeth Barksdale, Jie Chen, Nancy Dreyer, Lola Fashoyin-Aje, Elizabeth Garrett-Mayer, Nicole Gormley, Dr. Thomas Gwise, Lorenzo Hess,  Sumithra Mandrekar, Francesco Pignatti, Khadija Rantell, Andrew Raven, Yuan-Li Shen, Harpreet Singh, Craig L. Tendler, Marc Theoret, and Richard Pazdur

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum on April 8, 2021, and May 13, 2021, organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the United States Food and Drug Administration (U.S. FDA) Oncology Center of Excellence (OCE) and LUNGevity Foundation. In most cancer trials, disproportionately low numbers of older adults and certain racial minority groups are enrolled, even though a high incidence of cancer is observed in these subpopulations. This results in a lack of sufficient information on efficacy and safety of new treatments in such demographic subpopulations.

Discussions with a diverse group of stakeholders including oncologists, patient advocates, experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry focused on designing future pre- and post-market studies to evaluate treatment effect in demographically underrepresented (UR) cancer populations such as racial and ethnic minority groups and older adults. It is noted that often there is poor or no representation of pediatric cancer patients as well. However, not all adult cancers are observed in pediatric patients and vice-a-versa and these discussions mainly focused on adult cancers. It is recognized that inclusion of broader patient populations can introduce heterogeneity and if the trial includes patients with more comorbidities or poorer prognosis may increase the chances of rejecting an effective therapy. However, there are clinical trial designs and statistical methods to include and evaluate treatment effects in UR cancer patients. Importantly, a commitment and a concerted effort from all stakeholders to change the current practice is necessary to better understand the benefit/risk in these demographically UR patients in cancer clinical trials.

BMC Medical Informatics and Decision Making, 22 December 2022

LiSA: an assisted literature search pipeline for detecting serious adverse drug events with deep learning

Vincent Martenot, Valentin Masdeu, Jean Cupe, Faustine Gehin, Margot Blanchon, Julien Dauriat, Alexander Horst, Michael Renaudin, Philippe Girard, Jean-Daniel Zucker

Study to develop an augmented intelligence methodology for automatically identifying relevant publications mentioning an established link between a Drug and a Serious Adverse Event. The proposed pipeline, called LiSA (for Literature Search Application), is based on three independent deep learning models supporting a precise detection of safety signals in the biomedical literature.

Statistics in Biopharmaceutical Research (2022, VOL. 14, NO. 3, 353–357)

Use of Nonconcurrent Common Control in Master Protocols in Oncology Trials: Report of an American Statistical Association Biopharmaceutical Section Open Forum Discussion

Rajeshwari Sridhara, Olga Marchenko, Qi Jiang, Richard Pazdur, Martin Posch, Scott Berry, Marc Theoret, Yuan Li Shen, Thomas Gwise, Lorenzo Hess, Andrew Raven, Khadija Rantell, Kit Roes, Richard Simon, Mary Redman, Yuan Ji, and Cindy Lu

This article summarizes the discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum that took place on December 10, 2020 and was organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group, in coordination with the U.S. FDA Oncology Center of Excellence. Diverse stakeholders including experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry engaged in a discussion on the use of nonconcurrent control in Master Protocols for oncology trials. While the use of nonconcurrent control with the concurrent control may increase the power of detecting the therapeutic difference between a treatment and the control, the panelists had diverse opinion on the statistical approaches for modeling nonconcurrent and concurrent controls. Some were more concerned about the temporality of the nonconcurrent control and bias introduced by different confounders related to time, for example, changes in standard of care, changes in patient population, changes in recruiting strategies, changes in assessment of endpoints. Nevertheless, in some situations such as when the recruitment is extremely challenging for a rare disease, the panelists concluded that the use of a nonconcurrent control can be justified.

Journal of Pharmacy & Pharmaceutical Sciences 2022-10-08

A Survey of the Criteria Used for the Selection of Alternative Comparator Products by Participating Regulators and Organizations of the International Pharmaceutical Regulators Programme

Andrew Tam, Alfredo Garcia-Arieta, Ivana Abalos, Eduardo Agostinho Freitas Fernandes, Gustavo Mendes Lima Santos, Zulema Rodriguez Martinez, Milly Divinsky, Rami Kariv, Henrike Potthast, April C. Braddy, Clare Rodrigues, Erwin Guzman Aurela, Liliana Carolina Arevalo Gonzalez, Diego Gutierres Triana, Ben Jones, Choongyul Ahn, Hyuna Kim, So Hee Kim, Ryosuke Kuribayashi, Aya Myoenzono, Kohei Shimojo, Joy van Oudtshoorn, Cornelia Bigler, Ricarda Meincke, Matthias S. Roost, Chantal Walther, Li-feng Hsu, Christopher Crane, Tony Jarman

The objective of the review paper is to describe the criteria used by regulatory agencies that participate in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme when selecting an alternative comparator product for a previously accepted comparator product that was withdrawn from the market and is no longer available.

Statistics in Biopharmaceutical Research (2021, VOL. 00,NO. 0, 1–4)

Type I Error Considerations in Master Protocols With Common Control in Oncology Trials: Report of an American Statistical Association Biopharmaceutical Section Open Forum Discussion

Rajeshwari Sridhara, Olga Marchenko, Qi Jiang, Richard Pazdur, Martin Posch, Mary Redman, Yevgen Tymofyeyev, Xiaoyun (Nicole) Li, Marc Theoret, Yuan Li Shen, Thomas Gwise, Lorenzo Hess, Michael Coory, Andrew Raven, Naoto Kotani, Kit Roes, Filip Josephson, Scott Berry, Richard Simon, and Bruce Binkowitz

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the US FDA Oncology Center of Excellence on October 8, 2020. Diverse stakeholders including experts from international regulatory agencies, academicians, and members from the pharmaceutical industry engaged in a debate on Type I error considerations in master protocols with a common control. Although there were concerns in specific situations where Type I error adjustment may be necessary, the panelists agreed that adjustment of Type I error for multiplicity when a common control is used may not be necessary if the hypotheses are inferentially independent.

Journal of Pharmacy & Pharmaceutical Sciences 2021-10-15

Requirements for Additional Strength Biowaivers for Modified Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities

Matthias S. Roost, Henrike Potthast, Chantal Walther, Alfredo García-Arieta, Ivana Abalos, Eduardo Agostinho Freitas Fernandes, Gustavo Mendes Lima Santos, Zulema Rodríguez Martínez, Andrew Tam, Clare Rodrigues, Diego Alejandro Gutierrez Triana, Erwin Guzmán Aurela, Nayive Rodríguez Rodríguez, Sang Aeh Park, Jayoung Kim, Rami Kariv, Milly Divinsky, Ben Jones, Ryosuke Kuribayashi, Aya Myoenzono,  Miho Kasuga, Joy van Oudtshoorn, Jo-Feng Chi, Wen-Yi Hung, Li-Feng Hsu, Christopher Crane, Tony Jarman, April C. Braddy

The objective of the paper is to summarize the requirements of additional strength biowaivers of modified release solid oral dosage forms from participating Bioequivalence Working Group for Generics members of the International Pharmaceutical Regulators Programme.

Journal of Pharmacy & Pharmaceutical Sciences 2021-03-15

A Survey of the Regulatory Requirements for the Waiver of In Vivo Bioequivalence Studies of Generic Products in Certain Dosage Forms by Participating Regulators and Organisations of the International Pharmaceutical Regulators Programme

Craig Simon, Andrew Tam, Gustavo Mendes Lima Santos, Eduardo Agostinho Freitas Fernandes, Zulema Rodriguez Martinez, Clare Rodrigues, Sang Aeh Park, JaYoung Kim, Kwansoo Kim, Ryosuke Kuribayashi, Aya Myoenzono, Kohei Shimojo, Chantal Walther, Matthias S. Roost, Wen-Yi Hung, Li-feng Hsu, Christopher Crane, April C. Braddy, Joy van Oudtshoorn, Diego Alejandro Gutierrez Triana, Erwin Guzman Aurela, Ben Jones, Henrike Potthast, Ivana Abalos

The objective of the paper is to summarise the requirements to waive the in vivo demonstration of bioequivalence for oral solutions and suspensions, soft gelatin capsules and injectable products among the regulators and organisations that participate actively in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme.

Journal of Pharmacy & Pharmaceutical Sciences 2020-08-14

The Requirements for Additional Strength Biowaivers for Immediate Release Solid Oral Dosage Forms in International Pharmaceutical Regulators Programme Participating Regulators and Organisations: Differences and Commonalities

Christopher Crane, Gustavo Mendes Lima Santos, Eduardo Agostinho Freitas Fernandes, Craig Simon, Andrew Tam, Diego  Gutierrez  Triana,  Henrike  Potthast,  Ryosuke  Kuribayashi,  Yusuke  Okada,  Aya  Myoenzono,  Ivan  Omar Calderon, Zulema Rodríguez, Ben Jones, Sang Aeh Park, So Young Eum, Clare Rodrigues, Joy van Oudtshoorn, Arno Nolting, Chantal Walther, Matthias S. Roost, Jo-Feng Chi, Wen-Yi Hung, April C. Braddy, Alfredo García-Arieta

The objective of the article is to describe the differences and commonalities in biowaivers for additional strengths of immediate release solid oral dosage forms between the participating members of the International Pharmaceutical Regulators Program.

Journal of Pharmacy & Pharmaceutical Sciences 2019-01-01

A Survey of the Regulatory Requirements for the Acceptance of Foreign Comparator Products by Participating Regulators and Organizations of the International Generic Drug Regulators Programme

Alfredo García-Arieta,, Craig Simon, Gustavo Mendes Lima Santos, Iván Omar Calderón Lojero, Zulema Rodríguez Martínez, Clare Rodrigues, Sang Aeh Park, Ji Myoung Kim, Ryosuke Kuribayashi, Yusuke Okada, Arno Nolting, Chantal Pfäffli, Wen-Yi Hung, Christopher Crane, April C. Braddy, Joy van Oudtshoorn, Diego Gutierrez Triana, Mitch Clarke

The objective of the paper is to describe the current regulatory requirements with respect to the acceptability of foreign comparator products of oral dosage forms among the regulators/agencies that participate actively in the Bioequivalence Working Group for Generics of the International Pharmaceutical Regulators Programme and to identify those participants that may accept a foreign comparator product under certain conditions.

Journal of Pharmacy & Pharmaceutical Sciences 2018-03-30

A Survey of the Regulatory Requirements for BCS-Based Biowaivers for Solid Oral Dosage Forms by Participating Regulators and Organisations of the International Generic Drug Regulators Programme

Joy van Oudtshoorn, Alfredo García-Arieta, Gustavo Mendes Lima Santos,Christopher Crane, Clare Rodrigues, Craig Simon, Ji Myoung Kim, Sang Aeh Park, Yusuke Okada, Ryosuke Kuribayashi, Chantal Pfäffli, Arno Nolting, Iván Omar Calderón Lojero, Zulema Rodríguez Martínez, Wen-Yi Hung, April C. Braddy, Nancy Arciniegas Leal, Diego Gutierrez Triana, Mitch Clarke, Peter Bachmann

The objective of the paper is to describe the current BCS-based biowaiver regulatory requirements of the regulators/agencies that participate actively in the Bioequivalence Working Group of the International Generic Drug Regulators Programme, and to identify the commonalities and differences among these organisations.