Purpose

The purpose of the regulatory SIG is to co-ordinate regulatory activities across the European Pharmaceutical Statistical community and to engage with Regulatory statisticians.

Objectives

• Review of regulatory guidelines and policies to provide consolidated cross industry responses
• Identification of regulatory statistical issues that are concern across industry for discussion with regulators.
• Engagement on statistical issues with statisticians at the MHRA and EMA MWP 
• Promotion of best practice and driving debate on future guidelines

Who we are

How to get in touch

If you have any questions relating to Regulatory or need further information contact Jurgen Hummel (PSI co-chair) or Christoph Gerlinger (EFSPI co-chair). 

Meeting with Regulatory Agency Statisticians

We have been meeting annually with the MHRA statisticians for an informal exchange of statistical topics important for both regulators and industry since at least 2007.  Our most recent meetings were:

• 2019 (13 November): The main topics of the discussion were estimands, subgroup analyses and predefined Quality Tolerance Limits as well as quality attributes, model-based dose escalation studies, real world evidence, use of historical controls and the lack of statisticians in many ethics’ committees in England. Detailed minutes from the meeting were published in SPIN (Spring 2020).
• 2020 (19 November): For the first time the meeting was not held in person, but instead virtually via MS Team, which worked very well.  The main topics of the discussion were MHRA’s Future Drug Regulation Strategy, MHRA’s experience with COVID-19 and complex innovative designs as well as estimands, Real World Evidence, biosimilars, bioequivalence and Patient Reported Outcomes (PROs). Detailed minutes from the meeting were published in SPIN (Spring 2021) and can be found here.
• 2021 (17 November): As in 2020 the meeting took place virtually via MS Team, which again worked very well.  The main topics of the discussion were decentralized clinical trials, use of external controls, non-inferiority trials, estimands as well as the Post-Brexit regulatory world. Detailed minutes from the meeting were published in SPIN (Spring 2022) and can be found here.

• 2022 (23 November): Continuing with the format used during the previous 2 years the meeting took place virtually. The main topics of the discussion were planning for safety assessments, dose optimization in oncology and statistical methods for small populations.  Detailed minutes from the meeting were published in the PSI eNews and the EFSPI Newsletter shortly and can be found here.
• 2023 (8 November): Continuing with the format used during the previous years the meeting took place virtually. The main topics of the discussion were intercurrent events of treatment switching and its handling for long-term outcomes, subgroup analyses and considerations about acceptability of novel endpoints for regulatory decision making.  Detailed minutes from the meeting can be found here.

• 2024 (13 November): As in previous years the meeting took place virtually, but this time jointly with the EFSPI Statistical Methods Leaders. The main topics of the discussion were Bayesian statistics and inference in confirmatory trials (including for non-rare diseases and beyond paediatric trials) and Covariate adjustment in randomised clinical trials (including approaches based on ML).  Detailed minutes from the meeting can be found here.

Since 2013 we have also been meeting annually with the statisticians of the EMA Biostatistics Working Party for a similar exchange of statistical topics important for both regulators and industry.  The meeting held virtually on 2 October 2020 used a different format, as it was held jointly with other stakeholder organisations (which included EFPIA, AESGP, EGGVP, EUROPABIO, Animal Health Europe, Medicines for Europe and EUCOPE).  The discussion focused on the impact of COVID-19 on methodological aspects of on-going clinical trials and statistical methods applied to the quality of medicines, and minutes from the meeting can be found here.  Using a similar format, another meeting with several other statistical stakeholder organisations was held on 29 October 2021. This time the exchange focused on two topics only (raw data submissions and use of external control data) and therefore was better suited to an exchange of information than the previous year.  Minutes from the meeting can be found here.

Review of Regulatory Guidelines

One of the key activities is the review and collating of comments on key statistical documents, which was done in collaboration with other Special Interest Groups or cross-industry organizations (where appropriate).  This included the following documents:

2023:

• ICH draft guidance M11 on Clinical Electronic Structured Harmonised Protocol
• FDA draft guidance on Statistical Approaches to Establishing Bioequivalence
• FDA draft guidance on Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases (fda.gov)
• FDA draft guidance on Considerations for the Design and Conduct of Externally Controlled Trials for Drug and Biological Products (fda.gov)
• FDA draft guidance on Decentralized Clinical Trials for Drugs, Biological Products, and Devices
• FDA draft guidance on Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making
• EMA draft reflection paper on Establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation
• EMA draft Revised consolidated 3-year work plan for the Methodology Working Party (MWP)

2021:

• ICH’ draft reflection paper on patient focused drug development
• FDA’s draft guidance on Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biological Products

2020:

• EMA’s draft Points to Consider on implications of Coronavirus disease (COVID-19) on methodological aspects of ongoing clinical trials
• EMA’s draft guidance on registry-based studies:- comments provided here.

2019:

• EMA’s draft Questions and Answers on Data Monitoring Committees issues 
• EMA’s draft guidance on Qualification Opinion of Clinically Interpretable Treatment Effect Measures based on Recurrent Event
• FDA’s draft guidance in Interacting with the FDA on Complex Innovative Trial Designs for Drugs and Biological Products
• FDA’s draft guidance on Patient-Focused Drug Development: Methods to Identify What Is Important to Patients
• EMA’s draft guidance on Preparedness of Medicines' Clinical Trials in Paediatrics
• FDA’s draft guidance on Adjusting for Covariates in Randomized Clinical Trials for Drugs and Biologics with Continuous Outcomes
• The Center for Drug Evaluation in the NMPA (National Medical Product Administration) in China’s two draft guidelines on Clinical Trial Data Monitoring Committees and on Non-inferiority Clinical Trials.  

Events

Several SIG members have helped to organize the EFSPI workshop on Regulatory Statistics every year.  The most recent event was held face to face again from 14th to 15th September 2022.  We also contributed with to the poster session with a poster on the activities of the Regulatory SIG.  

On 21 October 2021 the PSI/EFSPI Regulatory SIG jointly organised together with the American Statistical Association Biopharmaceutical Section (ASA BIOP) a webinar on Complex Innovative Designs, which covered the following aspects:

• Overview of the FDA Complex Innovative Trial Design pilot program and the applications received to date together with details on some of them
• Overview of the FDA guidance on interacting on Complex Innovative Trial Designs
• Detailed case study of a clinical trial in children which was evaluated within FDA’s CID pilot program, applying borrowing of information from external trials in adults
• Overview of statistical and regulatory considerations on master protocols, focusing on Phase III confirmatory trials

The speakers were John Scott (FDA), Dieter Häring and Marius Thomas (Novartis) and Olivier Collignon (GSK), which was followed by a panel discussion chaired by Jürgen Hummel (PPD).  A video recording of the event and presentations can be found here. 

On 5 November 2020 the PSI/EFSPI Regulatory SIG jointly organised together with the American Statistical Association Biopharmaceutical Section (ASA BIOP) a webinar on Estimands, which covered the following aspects:

• Experience with proposals submitted to FDA and EMA on implementation of Estimands
• How the estimands framework facilitates interaction with clinicians in different therapeutic areas
• Common problems where the Estimands framework can help advance research
• Where further discussions and research is required, and particularly where industry and regulators can collaborate
• Issues related to alignment between different estimators to a given estimands
• Special considerations of estimand framework in COVID-19 vaccine trials.
  

The speakers were John Scott (FDA), Andreas Brandt (BfArM), Evgeny Degtyarev (Novartis) and Vladimir Dragalin (JNJ), which was followed by a panel discussion chaired by Anna Berglind (AstraZeneca).  A video recording of the event and presentations can be found here. 

On 4 July 2019, the PSI/EFSPI Regulatory SIG organized the webinar on ‘Adaptive design: updated draft FDA guidance and its implications’. In the webinar Jürgen Hummel (PPD) shared an overview of the FDA’s updated guidance on adaptive design for clinical trials of drugs and biologics, and discussed implications for industry. This was followed by the introduction of an open-source statistical software for adaptive designs, RPACT (an R package available on CRAN that enables the design and analysis of confirmatory adaptive clinical trials) led by Kaspar Rufibach (Roche). Kit Roes (Working Group Methodology of the Dutch Medicines Evaluation Board and member of the EMA Biostatistics Working Party) closed the webinar by commenting on the guidance from a European Regulatory perspective.