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.

International Symposium on Medicines and Patient Safety: Kigali, Rwanda – 5th November, 2014

Education on how to ensure safe and effective use of medicines is vitally important for patients and health services.
Registration and abstract submission on the themes below is now open for the International Symposium on Medicines and Patient Safety in partnership with Pharmacology for Africa. The symposium will take place on Wednesday 5th November 2014 in Kigali, the capital city of Rwanda, under the auspices of the College of Medicine and Health Sciences of the University of Rwanda.
 
The 3 major themes of the symposium are:

• Educating health professionals  in safe and effective use of medicines
• Regulating drugs, including pharmacovigilance and quality of medicines
• Reducing harm from high risk medicines and in patients with high risk conditions

University Hospital, Kigali

Key topics to be discussed and welcome as submitted abstracts include

• education in pharmacology and clinical pharmacology
• developing good prescribing skills
• developing rational treatment guidelines
• drug regulation including quality of medicines
• Drugs and Therapeutics Committees
• medicines for non-communicable diseases
• pharmacovigilance
• safe systems for using medicines for high risk therapeutic areas, including retroviral disease, maternal and paediatric health, cancer, and renal disease
• traditional medicines

This Symposium will be of particular interest to health professionals and policy makers

View over Kigali hills

interested in the safe and effective use of medicines.
These include doctors, pharmacists, nurses and managers working in referral, district and community hospitals, community pharmacists, experts interested in the safe regulation and supply of medicines, health professionals interested in pharmacovigilance, and educators interested in postgraduate and undergraduate training of health professionals in clinical pharmacology, therapeutics and safe dispensing.
The symposium will also be of interest to professionals working in NGOs and patient safety organisations concerned with public health and with disease prevention and treatment.

Drugs and Pharma: a matter of trust?

Medicines have significant costs, both financial and in terms of serious adverse effects. Treatment

should therefore only be prescribed and continued when the benefit outweighs the risk. This presupposes that health professionals, patients, and policymakers have trustworthy evidence to support clinical use of medicines.

It is vital that research on medicines is objective in order to show whether proposed treatments are effective for improving clinically meaningful outcomes for patients, how they compare to existing remedies, and the relative and absolute cost implications of adopting the treatment.

In his seductive polemic Bad Pharma, psychiatrist and 'Bad Science' Guardian columnist Ben Goldacre raises major concerns about the quality of evidence on the efficacy and safety of specific drugs and classes of treatment in clinical use. His book has added to recent public concern about medicines, their safety, and the probity of pharmaceutical companies.

This background concern for the public has been inspired both by works of fiction, for example the film Side Effects, set within a corrupted psychotherapeutic sector, and John Le Carre's African novel The Constant Gardener, which raises important questions about the ethics of clinical research on anti-infective agents in developing countries.

And by a series of very large fines imposed on major pharmaceutical companies for a wide range of reported major errors of omission and commission, including concealed data on safety, and encouragement of doctors to prescribe off-licence, i.e. to patient groups for whom there is no or insufficient evidence on effectiveness or safety of medicines.

See more in reviews in the Reinvention Journal

Ben Goldacre Bad Pharma: How drug companies mislead doctors and harm patients.
London: Fourth Estate. Reprinted with edits: February 5, 2013 | ISBN-10: 0865478007 | ISBN-13: 978-0865478008

New EU black triangle scheme for medicinal products

There are several key stages in use of medicines and vaccines in clinical practice when reporting on clinical experience of side effects and suspected adverse effects is particularly important.

In addition to a duty to report any serious adverse effect, times to be particularly vigilant include when a medicine has just been launched; when indications for use are changed – ie new patient groups are exposed to the medicine; special patient populations for whom experience of a medicine may be limited – e.g. children; new combinations with the treatment, with which unexpected drug interactions may occur. 

The European Medicines Agency [EMA] notes these additional categories: “ it contains a new active substance authorised in the EU after 1 January 2011; it is a biological medicine, such as a vaccine or a medicine derived from plasma (blood), for which there is limited post-marketing experience; it has been given a conditional approval (where the company that markets the medicine must provide more data about it) or approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data); the company that markets the medicine is required to carry out additional studies, for instance, to provide more data on long-term use of the medicine or on a rare side effect seen during clinical trials.”

A Black Triangle logo has been used in the UK for many years “to signify medicines that are subject to intensive monitoring" [MHRA]. This inverted Black Triangle logo will now be used in all EU Member States, with a list of 'Black Triangle' medicines and vaccines agreed Europe-wide, the first version released in April 2013. The Black Triangle will start appearing in the package leaflets of medicines concerned from autumn 2013.

See more on the EMA website on the new European Union wide black triangle scheme for medicinal products and vaccines,

 indicating that they should be subject to additional monitoring and reporting by health professionals and patients.

Shakespeare's Medicine Cabinet discussed at the Dana Centre

@HealthMed: Shakespeare’s Medicine Cabinet was the theme of a packed evening session at the Dana Centre on 8^th November. The Dana Centre is funded as joint venture with the Science Museum and Imperial College London, with the aim of bringing together the public with academics and other experts to discuss a wide range of themes.

This evening explored, with the help of the excellent Dana Actors (directed by Silvia Ayguade), facts and fantasy underlying effects of plants as medicines, poisons and aphrodisiacs in Shakespeare’s plays.

Professor Rod Flower FRS selected examples from Macbeth, Midsummer Night’s Dream and Romeo and Juliet, asking the question whether botanical references were ‘merely dramatic license, or was there a scientific basis for the use of drugs in his plays?’ For example Juliet imploring the Friar:

“… Let me have a dram of poison, such soon-speeding gear 

As will disperse itself through all the veins 

That the life-weary taker may fall dead …”

And the Friar’s offer of a specific death-mimicking toxin to last ‘… two and forty hours …’

Love-in-idleness

The interval was spiced with the opportunity provided by the British Pharmacological Society organisers to sample some of the healthier plants mentioned, including an interesting Heartsease floral tea – the plant referred to as ‘love-in-idleness' by King Oberon in Midsummer Night’s Dream.

Dr Randolph Arroo, Head of Research at the School of Pharmacy in Leicester, went on to discuss the interface between plants and medicines in the second Elizebethan Age.

His comments on reliability of plant sources and earlier issues raised by Professor Flower were echoed in the discussion points raised by a very engaged and informed audience.

For more see the Dana Centre website

and the website of co-organiser the British Pharmacological Society.

What's in a medicine?

@HealthMed Most of the weight of a tablet or capsule consists of coatings and fillers to make the enclosed active ingredient is big enough to pick up. Some common medicines such as the heart tablet digoxin or thyroid replacement treatment may have an active ingredient weight of as low as one tenth of a gram - ie it might take around 50 doses to fill a level teaspoon.
That raises the obvious question: what other ingredients are present in medicines? The range of fillers includes usually harmless chemicals such as the sugar lactose. That could prove a problem with patients who suffer lactose intolerance - due to immaturity in or loss of the enzyme needed to break down lactose.
And liquids or tablet coatings may include animal extracts, in the form of gelatin. Although this should be clearly labelled on the package insert that should accompany all medicines, a paper in the latest issue of the Postgraduate Medical Journal has reported that many patients on restricted diets are unaware of this.
The study in the Postgraduate Medical Journal reported that a quarter of patients surveyed who were on restricted diets were unaware that they had been prescribed drugs containing gelatin, contrary to their wishes or beliefs as vegetarians, or for other cultural or religious reasons.
If not clear from the packaging, patients should ask their pharmacist for further information on the non-drug contents of medicines prescribed, or bought over the counter without a prescription.

See BBC report on the PMJ article