European Medicines Agency advises continued use of medicines to treat hypertension, heart failure and kidney disease

27.3.20: Briefing from the European Medicines Agency

EMA reports that it is aware of recent media reports and publications which question whether some medicines, for instance angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs, or sartan medicines), could worsen coronavirus disease (COVID-19). ACE inhibitors and ARBs are most commonly used for treating patients with high blood pressure, heart failure or kidney disease. 

The EMA has providing the following advice from its Public and Stakeholders Engagement Department.

"It is important that patients do not interrupt their treatment with ACE inhibitors or ARBs and there is no need to switch to other medicines. There is currently no evidence from clinical or epidemiological studies that establishes a link between ACE inhibitors or ARBs and the worsening of COVID-19. Experts in the treatment of heart and blood pressure disorders, including the European Society of Cardiology, have already issued statements along those lines. To gather more evidence, EMA is proactively reaching out to researchers working to generate further evidence in epidemiological studies.

As the public health crisis rapidly extends across the globe, scientific research is ongoing to understand how the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reproduces in the body, interacts with the immune system and causes disease, and whether ongoing treatment with medicines such as ACE-inhibitors and ARBs could impact the prognosis of COVID-19.

The speculation that ACE-inhibitors or ARBs treatment can make infections worse in the context of COVID-19 is not supported by clinical evidence. These medicines work by affecting the renin-angiotensin-aldosterone system (RAAS). Because the virus uses a target called angiotensin converting enzyme 2 (ACE2), which is part of this system, to enter human cells, and the medicines can increase ACE2, one of the suggestions among others is that they could also increase virus activity. However, the interactions of the virus with the RAAS in the body are complex and not completely understood.

EMA is monitoring the situation closely and is collaborating with stakeholders to coordinate epidemiological studies on the effects of ACE inhibitors and ARBs in people with COVID-19.

EMA is helping to coordinate urgent ongoing research and is fully committed to keep the public up to date with any development in this field. EMA is also aware of reports questioning whether other medicines such as corticosteroids and non-steroidal anti-inflammatories (NSAIDs) could worsen COVID-19, and has recently issued a communication on NSAIDs medicines. It is important that patients who have any questions or are uncertain about their medicines speak to their doctor or pharmacist and do not stop their regular treatment without speaking to their healthcare professional first.

Medicines should be prescribed and used in line with clinical judgement, taking due note of any warnings and other information provided in the summary of product characteristics (SmPC) and thepackage leaflet, as well as guidance issued by the WHO and relevant national and international bodies.

Within the EU medicines regulatory network, evidence on the safe use of medicines is reviewed as it emerges. Any new advice that arises is disseminated appropriately through EMA and national competent authorities.

EMA will provide further information as appropriate.

This information and related content are published here. Please check EMA’s dedicated webpage on COVID-19 for the latest updates."

Still time to submit an abstract for the EACPT Congress in Sweden: 29th June to 2nd July 2019

The next EACPT Congress will be held from 29th June to 2nd July in 2019 in Stockholm as a partnership between the EACPT and the Swedish Society for Pharmacology, Clinical Pharmacology and Therapeutics. 

The Congress will address Tomorrow’s Healthcare Challenges and will be held at the City Conference Centre – 5 minutes from Stockholm Central Station.

Abstract closing date extended to 14th March.

Register online 

The Congress Reception on the evening of Saturday 29th June, will be held at Stockholm City Hall, the venue of the Nobel Prize banquet.

The Keynote Opening Lecture will be given by the President at the Karolinska Institute, Professor Ole Petter Ottersen, on global health and clinical pharmacology.

Around 60 invited speakers are expected from throughout Europe and beyond. Congress keynote lectures, sessions and themes will include:

• Advanced therapies
• Chronic disease
• Clinical pharmacologists versus computers
• Closing the money gap
• Drug regulation in the 2020’s
• EACPT meets Asian Societies
• EPHAR-EACPT joint symposium on personalised medicine
• Ethics in clinical research
• Global Health
• How to become a clinical pharmacologist
• How to measure drug exposure
• How to measure drug use
• How to perform a health economic study
• Interprofessional exchange for better drug treatment
• Misuse of medicines
• Patient empowerment
• Preparing tomorrow’s prescribers
• Prescribing and deprescribing
• Targeting small populations
• The critically ill patient
• Treating ageing populations
• Treating cancer
• Treating children

Major awards to be presented at the Stockholm Congress include the EACPT Lifetime Achievement Award and the biennial EACPT Scientific Award for best publication on a clinical pharmacology or therapeutic theme.

Opportunities for EACPT Associate Members include
* discounted registration fees for EACPT meetings
* networking with colleagues worldwide through the global EACPT network of Associate Members
* active involvement in EACPT Working Parties and other activities

Find out how to become an Associate Member of the EACPT

Future EACPT Congresses will be held in:
– 2021 Athens
– 2023 Rotterdam

The EACPT was founded in 1993 and now includes as members all national organisations for clinical pharmacology in Europe, as well as organisations from further afield internationally. The EACPT aims to provide educational and scientific support for the more than 4000 individual professionals interested in clinical pharmacology and therapeutics throughout the European region, with its congresses attended by a global audience. The EACPT also advises policy makers on how the specialty can contribute to human health and wealth.

Developing robust common data models to guide safety in medicines in Europe

The European Medicines Agency held a 2 day international workshop in London [11th -12th December 2017] to define the opportunities and challenges around implementation of a common health data model in Europe to support regulatory decision making. The expected outcome of the workshop was agreement of guiding principles for the development of a Common Data Model (CDM) in Europe, including key criteria for validation in the context of regulatory decision-making.

A common data model could help harmonise healthcare data across multiple data sets and provide a mechanism to conduct pan-European studies in a timely manner to address regulatory questions. At the same time, applying a common model to European data has multiple challenges. The meeting brought together regulators with academia, data holders and the pharmaceutical industry.

Sessions included talks from experts from North America (FDA, Harvard, Duke, Georgia Tech ...) and the European region (Erasmus, Utrecht, CBG-MEB, EMA ...) discussing lessons learned and current challenges in very large current clinical data resources, regulatory verification and related issues. Common data model case studies considered included Sentinel – the Harvard-based FDA system for accessing patient data from 16 health data partners across the USA and CNODES (the Canadian Network for Operational Drug Effect Studies) which can access data on 100 million patients – a similar scale to Sentinel.

The U.S. Food and Drug Administration's (FDA) Sentinel Initiative is a long term approach which uses a common health data model to improve the FDA’s ability to identify and explore safety issues for medical products. Sentinel actively surveys pre-existing electronic healthcare data from multiple sources.

Consistent themes included ensuring the relevance of evolving common data models to health policy, keeping timelines as short as practical, interoperability, consent and related ethical issues (data custodians, patient data protection and privacy), and careful internal and external validation of clinical definitions, data, software and analytical models.

From the perspective of health professionals, policy makers, regulators and the public, key questions included whether clinical outcomes from common data models are generalisable or only relevant to specific sub-populations based on geography, genetics, demographics and/or complex co-morbidity.  In the era of precision medicine there is the clear need is to avoid “right” answers from the wrong clinical populations and “wrong” answers from the right populations.

Further key points considered included: what is the cost of developing and maintaining validated CDMs; who should pay; whether updating existing databases is a sufficient approach or rather new more robust databases are needed.

See more about the workshop

Impact of decision to move European Medicines Agency to Amsterdam

As one of many consequences of Brexit, following a very close vote by member states on Monday 20th November, Amsterdam has been confirmed as the new home for the European Medicines Agency. On current plans, the EMA will be operating in Amsterdam from April 2019, following a likely shadow hosting of the EMA there for some months before the formal date for completing the move of the agency.

The EMA's Patients and Consumers Working Party annual meeting

Meantime the EMA's Patients and Consumers Working Party (PCWP) is holding its annual meeting with all EMA eligible patient/consumer consumer organisations to consider relocation preparedness, patient and consumer involvement in EMA activities, highlights from major EMA committees and updates on pharmacovigilance, information on medicines and future work programmes in 2018 and 2019 for the PCWP and the EMA's Healthcare Professionals Working Party.

Effective medicines have both powerful therapeutic actions as well as the potential for serious unwanted adverse effects. The EMA was founded in 1995 with initial funding from the European Union and the pharmaceutical industry, and further support from EU member states. The European Medicines Agency is concerned with regulation, supply chain and pharmacovigilance for medicines and other advanced therapies for 28 countries across the European Union - from the Baltic countries to Ireland and from Scandinavia to the Balkans and the Mediterranean. All these roles concern balancing benefits and risks when it comes to patient safety with regard to medicines.

The EMA has established mechanisms for involving patients in regulatory assessment: patients’ value perception and value systems. The EMA also has an increasing remit to engage with stakeholder organisations and to improve transparency in its activities for the ~510 million citizens of the European Union. Furthermore the EMA has a major role in educating patients, carers and health care professionals about medicines. There have for example been recent workshops on

• combating antibiotic resistance: a partnership with the European Centre for Disease Control 
• biosimilars
• personalised medicine initiatives
• applying big data to improved regulation of medicines in Europe which raises important questions about clinical utility, quality, accessibility and systems for data mining

There remain many decisions and actions for the coming months needed to ensure continuity of the EMA's business. These involve the smooth relocation of the EMA to Amsterdam and either developing systems to retain UK expertise for the EMA or replacing that expertise from other EU member states. For the EMA, priorities include:

• minimising the impact on staff of the move to maximise staff retention
• maintaining capacity to continue the work of the EMA 
• the resulting need to prioritise EMA core and planned further activities
• continuing productive engagement with stakeholder groups: patients, carers, healthcare professionals ...
• maintaining the capacity of the EMA to engage with the public

For the UK, there are pressing questions regarding the future regulation of medicines in the UK post-Brexit, the impact of loss of international influence of UK regulators and other experts on medicines and the impact of loss of biotech and pharmaceutical companies from London to Amsterdam.

The EMA has been based in London for over 20 years. Many staff have strong family and other personal ties in the UK - for example partners' work, children at school, dependent relatives ...  Adapting to a new country is no simple matter. The working language of the EMA is currently English however full integration within Amsterdam will need competency in the native language in the Netherlands. There will also be practical challenges arising from the simultaneous impact of the arrival of up to 800 families on the Amsterdam housing market and schools system.

© Donald Singer 

ADAPTSMART: Accelerated Development of Appropriate Patient Therapies

ADAPT SMART is a  platform funded by the European Union's IMI (Innovative Medicines Initiative) for the coordination of Medicines Adaptive Pathways to Patients (MAPPs) activities, involving multi-stakeholder approaches from research through to treatment outcomes. MAPPs seek to foster access to beneficial treatments for the right patient groups at the earliest appropriate time in the product life-span in a sustainable fashiion.

The European Medicines Agency has just hosted (17th - 18th  January 2017) at Canary Wharf in London an expert workshop on ADAPTSMART, with delegates from throughout the European Region, from the Japanese medicines agency and elsewhere.

Topics included:

- appropriate use of medicines

- timely access to innovative medicines and other interventions

- early access medicine schemes

- protected therapeutic schemes e.g. cancer access funds

- compassionate use

- expanded access pathways

- shortened timelines for approvals

- need for cross-border data-sharing and research

- international comparisons for consequences of inappropriate prescribing - non-compliance with treatment guidelines

- linkeing reimbursement to compliance with prescribing guidelines

See more on the ADAPTSMART website about key work packages and other aspects.

Adaptive pathways: new ways to assess treatments for serious unmet medical need

The European Medicines Agency hosted a stakeholder workshop on 8th December 2016 on adaptive pathways at its Canary Wharf London headquarters: a hot topic with around 150 delegates from healthcare, patient and consumer organisations, academia, industry and regulatory bodies.
The European Medicines Agency organised this workshop in collaboration with the European Commission to gather views and proposals from stakeholders on the adaptive pathways approach, in light of the practical experience gained during the pilot project EMA ran between March 2014 and August 2016, and to plan the next steps in the exploration of this concept. 

The basis for considering adaptive pathways for evaluating medicines is to meet the challenges underlying how to resolve high unmet medical need with then aim of licensing products likely to have a major impact on patient morbidity and/or life expectancy.
The desire is to find ways to reduce unavoidable uncertainties as rapidly as possible for serious/rare debilitating and life-shortening illnesses. There are clear ethical and scientific challenges in using novel approaches to evaluate medicines without a decline in the quality of evidence on the effectiveness and safety of new treatments. 

Products which might be considered for use of adaptive evaluation pathways include both conventional medicines and advanced therapy medicinal products (ATMPs). ATMPs are medicinal product which involve either a gene therapy medicinal, a somatic cell therapy or a tissue engineered product [see more on ATMPs at Directive 2001/83/EC as amended by the ATMP Regulation 1394/2007].

Adaptive pathways contribute to an expanded  toolbox for evidence generation where conventional randomized controlled trials are not-appropriate or practical. Principles include using processes to allow rapid reaction to uncertainty by iterative development based on ongoing analysis of  pathway data [“rapid cycle analysis”]. As secondary end-points are welcomed, these pathways require pre-planning across the entire product life-span, including the post-marketing paths ie active monitoring and management of on-market use.

The adaptive pathway approach is dependent on earliest stage and ongoing multi-stakeholder networking, underpinned by risk management plans. 

Critical issues include
- resolving scientific trust in real world data and the need to develop mature, robust registries
- defining and prioritising unmet medical needs
- agreement on acceptable risks and benefits early access worth it (vs.
- maintaining safety standards
- ensuring that benefits outweigh risks
- avoiding unrealistic expectations
- establishing practical criteria for reimbursement, especially when secondary outcome measures form the basis for market authorization  

Safer Big Data for safer medicines?

14-15 November, 2016: The European Medicines Agency invited experts from the European Union and the USA to discuss 5 key perspectives to speak on Big Data at a workshop in London aimed at identifying opportunities from 'Real World and other "Big Data" to improve development of new medicines and surveillance of licensed medicines for safety, risk and effectiveness.

The 5 key 'stakeholder' perspectives? Patients and the public, health professionals, academia, regulators and policy makers, industry (both health sector and software/hardware) and payers (considering a change in strategy to payment for health impact rather than sales, as exemplified by the Health Impact Fund).

A pragmatic definition from Lu and his colleagues states that "Big data analytics (BDA) applications are a new category of software applications that process large amounts of data using scalable parallel processing infrastructure to obtain hidden value." There are many potential applications from planning for public transport flows to using large health record datasets to improve patient safety such as in the US FDA-Harvard Sentinel partnership.

The FAIR principles for Big Data, Finding, Accessing, Interoperability and Reuse of Big Data, have both general and special challenges and potential benefits when applied to healthcare.

For example, in a recent issue of Nature Reviews Cardiology, Rumsfeld and colleagues from Colorado and Boston outline 8 potential applications of big data analytics to improve cardiovascular care, including "predictive modelling for risk and resource use, population management, drug and medical device safety surveillance, disease and treatment heterogeneity, precision medicine and clinical decision support, quality of care and performance measurement, and public health and research applications".

The EMA note: "Rapid developments in technology have led to the generation of vast volumes of data, which have the capability to transform the way the benefit-risk of medicinal products is assessed over their entire life cycle. However, it is recognised there are multiple challenges in the exploitation of these data.

"These range from the fundamental need to establish methods to enable the access to, integration and analysis of heterogeneous datasets to understanding the limitations in its use. Importantly, robust and transparent mechanisms to protect patient confidentiality are key to secure patient trust. It is important for the European Medicines Agency and the European Union medicines regulatory network to gather information on the latest developments in big data from the perspective of all stakeholders in order to identity how and when the multitude of data sources may contribute to medicinal product development, authorisation and post-marketing surveillance."

Some key themes:
- Patrick Ryan on which patients chose which treatments
- Sophie Louveaux discussing new EU regulation of data, meaningful consent and processing sensitive health data
- David Martin addressing challenges in Big Data analytics from FDA and PPP perspectives
- Julian Isla from the Dravet patient charity on making the patient the centre in digital health
- Baroness Helene Hayman on ethics, governance and public confidence
- Ronald Brand from the University of Leiden on informed consent v. opt out
- Nicolas Tatonetti from Columbia University, NY on data mining for medical discovery
- Nico Gaviola from Google on cloud data for safer medicines

See more on key threads and discussion points including on the European Open Science Cloud, new EU General Data Protection Regulations - from May 2018, replacing Directive 95/46, machine-learning for chemogenomics, challenges to implementing applications to precision medicines, access to the OHDSI community, social media to find new adverse drug event signals, FDA case studies using then Sentinel-HMO-Harvard collaboration,  opening access to the 28 EU independent national health care systems and more in due course when talks are made available on the EMA website for public access.

Safer medicines in children and adults: video discussions from the international 2016 EACPT Focus Meeting in Opatija

From the EACPT Focus Meeting on How to Assess Medicines, Opatija, 6-9 October 2016. 

In these videos, Donald Singer discusses with speaker Suzana Mimica Matanovic evaluation of drugs in the pediatric population with an update on the impact of recent initiatives from the European Medicines Agency and discusses with Janne Backman from Helsinki how to identify and minimise risk of drug-drug interactions.

 

Discussants

- Suzana Matanovic: Assistant Professor of Clinical Pharmacology, School of Medicine, University of Osijek, Croatia and PCO alternate delegate at the European Medicines Agency

- Janne Tapio Backman: Professor in Clinical Pharmacology and Individual Medicine, University of Helsinki, Finland

- Professor Donald Singer: member of the Executive Committee of the European Association for Clinical Pharmacology and Therapeutics and EACPT delegate on the European Medicines Agency Health Professionals Working Party. 

Here is a summary of the key points from Professor Backman's  talk at the EACPT Focus Meeting in Opatija: 

Drug-drug interactions can either markedly reduce or enhance the therapeutic or adverse effects of drugs by causing alterations in the pharmacokinetics or pharmacodynamics of drugs. If such interactions are not understood or accounted for in patient care, they can have harmful, even hazardous clinical consequences. 

Drug-drug interactions have been a major cause of drug withdrawals from the market. Regulatory agencies, including the European Medicines Agency (EMA) have therefore published guidance documents that are designed for the industry to guide their DDI studies during drug development. In particular, detailed scientific recommendations can be given concerning pharmacokinetic interactions, because such interactions can be mediated via mechanistic changes in absorption, distribution, metabolism and excretion of drugs. 

Specific approaches are suggested concerning cytochrome P450 enzymes (CYPs), non-CYP enzymes and membrane transporters. In addition, current guidance also recommends use of modelling approaches, such as physiologically based pharmacokinetic (PBPK) models to design and extend the interpretation of preclinical and clinical drug-drug interaction studies. For designing clinical drug-drug interactions studies, detailed preclinical in vitro and early clinical pharmacokinetic information is necessary. 

Despite detailed guidelines, there are many challenges in characterization of the interaction potential of a drug, both as a perpetrator and as a victim of the interaction. Such challenges arise from complex interaction mechanisms, eg, simultaneous involvement of transporters and drug metabolizing enzymes, autoinhibition and autoinduction of metabolism, time-dependent inhibition and involvement of major drug metabolites. 

Understanding the challenges and pitfalls of drug-drug interaction studies is thus necessary in interpretation of the results of studies. In this lecture, basic methods of clinical drug-drug interaction studies will be reviewed, with examples of potential pitfalls and basic principles of interpretation.

The next EACPT biennial congress will be held in Prague Congress from 24th - 27th June 2017. The programme will provide an international scientific and educational forum for discussion of clinical pharmacology and therapeutics, including personalised pharmacotherapy. See more on our website. 

Anyone from anywhere in the world with a professional interest in clinical pharmacology and therapeutics can now join the EACPT as an Individual Associate member.

Membership benefits include

* Access to videos of talks from EACPT Meetings

* Discounted registration fees for EACPT meetings

* Online access to the Official EACPT Journal - Clinical Therapeutics

* Access to the EACPT’s worldwide network of Individual Associate Members

* Active involvement in EACPT 

The EACPT was founded 24 years ago and now includes as members all national organisations for clinical pharmacology in Europe, as well as organisations from further afield internationally. The EACPT aims to provide educational and scientific support for the more than 4000 individual professionals interested in clinical pharmacology and therapeutics throughout the European region, with its congresses attended by a global audience. The EACPT also advises policy makers on how the specialty can contribute to human health and wealth.

Research finds new target in search for why statin drugs may cause problems for some patients

10th February, 2016
Research by the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW), and Tangent Reprofiling Limited, has discovered that statin drugs interact with a gap junction protein called GJC3 that releases ATP, a major signaling molecule for inflammation in the body.  This discovery provides a significant new target in the search for why statin drugs can sometimes cause harmful effects such as muscle toxicity in some patients.

GJC3 gap junction proteins

Speaking on behalf of the team in the Department of Chemistry at the University of Warwick, Dr Andrew Marsh said:

“Statins are powerful cholesterol-lowering medicines that are widely prescribed to reduce the burden of cardiovascular disease. Gap junction proteins are important in forming communication channels between cells and organs in the body. In this new research, two clinically used statin therapeutics have been found to interact with an important part of GJC3, a gap junction protein which acts to release ATP, a signaling molecule that is key to the body’s response to injury and inflammation.

“Many people know ATP as the cell’s main energy transfer molecule, but when released outside cells, ATP coordinates how tissues including our liver and muscles deal with recovery from injury. These results may give us better understanding of how some of the harmful effects of statins in some patients, such as muscle toxicity, might come about”.

The new research paper entitled “Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein” http://dx.plos.org/10.1371/journal.pone.pone.0148266 is published on Wednesday 10th February 2016 in the open access journal PLOS ONE. The study was a collaboration between scientists and clinicians at the University of Warwick, the University Hospital Coventry and Warwickshire NHS Trust (UHCW) and Tangent Reprofiling Limited.

The researchers found that the statins simvastatin sodium salt and fluvastatin were found to interact with a peptide from the gap junction protein GJC3. In work which confirmed the observed interaction, the researchers also found that certain pharmacological probes of other gap junction proteins are also bound to the peptide sequence they had identified. The orange colour in the Figure highlights the important portions of GJC3 gap junction proteins.

University of Warwick research chemist Dr Andrew Marsh also said that

“GJC3 is present in many tissues in the body, but its role in cell signaling is poorly understood. Our work opens doors to its investigation”.

Professor Donald Singer, President of the Fellowship of Postgraduate Medicine and who was the lead investigator of the teams working on this study in Warwick Medical School and UHCW commented

“Finding additional ways in which statins act at the cellular and molecular level is important for giving clues to potential new medical applications for these drugs. 

"These results may also give us better understanding of how some of the harmful effects of statins in some patients might come about”.

Notes for editors:

The research refers to the open access journal PLOS ONE paper http://dx.plos.org/10.1371/journal.pone.pone.0148266, 10 Feb 2016 and the paper was entitled Simvastatin sodium salt and fluvastatin interact with human gap junction gamma-3 protein”. PLOS ONE publishes work from science and medicine and “facilitates the discovery of connections between research whether within or between disciplines”.

The work was funded by the Engineering and Physical Sciences Research Council (EPSRC, UK), the University of Warwick and Tangent Reprofiling Limited. EPSRC’s vision is “for the UK to be the most dynamic and stimulating environment in which to engage in research and innovation.”

https://www.epsrc.ac.uk/about/facts/mission/

Equipment used in this research was obtained through Birmingham Science City: Innovative Uses for Advanced Materials in the Modern World with support from Advantage West Midlands (AWM) and part funded by the European Regional Development Fund (ERDF).

For further information please contact:

Dr Andrew Marsh,

Department of Chemistry, University of Warwick, Coventry CV4 7AL. Tel. +44 24 7652 4565

a.marsh@warwick.ac.uk

 or

 Peter Dunn, Director of Press and Policy,

 University of Warwick, Tel UK: 024 76523708 office 07767 655860 mobile

 Tel Overseas: +44 (0)24 76523708 office +44 (0)7767 655860 mobile/cell

 Email: p.j.dunn@warwick.ac.uk

PR31 PJD 9^th February 2016