Purpose

The purpose of the regulatory SIG is to co-ordinate regulatory activities across the European Pharmaceutical Statistical community and to engage with European 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.
• Regular engagement on statistical issues with statisticians at EMA Biostats Working Party and MHRA 
• 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 will be published in the Spring 2021 edition of SPIN.

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.  Due to EMA’s business continuation plan for Brexit no meeting was held in 2019, and the most 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.

Review of Regulatory Guidelines

One of the key activities is the review and collating of comments on key statistical documents, which included the following:
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 virtually on 12 and 13 October 2020, focusing on Data Monitoring Committees and Estimands.  

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.