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.

Not so smart drugs: concerns about modafinil

Modafinil has been in medical use since the late 1980s to improve alertness.

Because of concerns about serious medical risks, medical use has been restricted to treating narcolepsy since 2010 by the European Medicines Agency and the UK's Medicines and Healthcare products Regulatory Agency.

Students and employees, young and old, are being tempted to use 'smart' drugs to try to improve their academic or professional performance. This use of modafinil is not medically licensed - the aim of improving the effectiveness of learning and performance in exams, and other educational assignments.

The drug is reported to be in widespread use by students in Germany, the UK, the US and elsewhere in the hope that it will improve studying, learning and exam performance.
 

How is modafinil thought to act? Its mode of action is unknown. Suggested mechanisms include orexin-mediated enhancement of a range of brain activation neurotransmitters (norepinephrine, dopamine, histamine, serotonin) in brain arousal centres; and increased gap junction communication from brain cell to brain cell.

Does modafinil improve intellectual performance? At best, it is considered no substitute for a healthy sleep pattern. There have been two types of formal study – those in well-slept healthy young or older subject; and studies in sleep deprived subjects. Typically, studies are of a single dose, and medical or psychiatric disorders, and use of other medical drugs, or recreational drugs (including caffeine, alcohol and nicotine) are reasons for exclusion from studies of modafinil.

Studies of possible effects of modafinil on studying and learning are typically based on artificial tests – ie do not test for possible benefits of the drug on what students may be trying to learn, or results of the types of exams students may be sitting. Results are conflicting. In high IQ young subjects, performance of highly complex psychological tests, but not less complex tasks, may be improved. More focused study, with however increased response time has also been reported.

Anecdotally, students have reported that the drug appears to lead to more efficient completion of a deadline but not improvement in content. However these perceptions are vulnerable to placebo responses.

Only a handful of good quality studies have been performed on the possible effects of modafinil on cognition. These have involved psychological model tests, not studies of how well students learn course or professional materials. There remains the need for study of effects and risks of repeated use of modafinil in real world settings using tests relevant to the study activities of students.

Side effects? There are many – from loose bowels, to loss of effectiveness of the oral contraceptive pill, leading to unwanted pregnancy, and rare but life-threatening and fatal skin reactions Stevens-Johnson Syndrome).

Further important side effects include sleep disturbance and neuropsychiatric disorders indirect reasons why performance might be impaired by the drug.

There are also reports by users that in response to modafinil too much focus on details may make it difficult both to complete an assessment and to consider a broad enough range of issues to give a complete answer.

Risks of modafinil may be greater if there are unrecognized problems, in particular if the user has a medical history of cardiovascular or psychiatric problems. Use without clinical advice may mean that important underlying conditions are not identified, for example high blood pressure, disorders of heart rhythm, and psychiatric risk; and potential important interactions with other drugs (including other stimulants) may not be considered.

Modafinil has clinically significant effects on the activity of liver enzymes and drug transporters which are important in the handling and clearance of a wide range of common drugs, including digoxin and warfarin.

Older people are more likely to have medical disorders and to be on treatment which might lead to increased risk from modafinil. A particular concern is that these markers of increased risk may not be considered when off-licence supplies are being sought in the hope that there may be benefit for professional work, or as an aid to studying – for example for revalidation.

  
Is use of modafinil any different from using caffeine? Because of the lack of convincing evidence of real world benefit from modafinil and concerns about serious risks, the drug is not approved for use in the absence of a specified medical condition. There are to date no convincing studies showing a benefit from modafinil in long-term use or for specific types of learning or testing relevant to students.

As for other drugs, the balance between risk and benefit must be considered by prescriber and user. In the event of any benefit for studying from the drug, others not using it are put at a disadvantage. 

In contrast caffeine is widely available for those who chose to use it. Too much caffeine, or sensitivity to caffeine can cause troublesome symptoms, including anxiety, tremor, sleep disturbance and palpitations.

Risks from accessing modafinil  from internet pharmacies? For the above reasons, licensed pharmacies would not supply modafinil in the absence of specified medical conditions. Unlicensed internet pharmacies should be avoided. The quality of medicines is not reliable, with serious risk of being supplied poorly active or counterfeit or contaminated medicines. And medical contra-indications need to be identified and discussed to minimize the risk of preventable serious adverse effects.

Fairness and coercion There are also a number of ethical concerns including: the need to protect students and others from using so-called ‘smart drugs’ in response to pressure to compete, both in exams and in professional life; being fair to other students who do not have access to the drug, or do not wish to use what may be a medically harmful pharmacological aid to improving performance in examinations or to meeting challenges at work.

See also
- June 2009: Opposing opinions in the British Medical Journal from John Harris and Anjan Chatterjee

-  Methylphenidate (Ritalin) – does use by ‘healthy’ students matter?

Methylphenidate (Ritalin) – does use by ‘healthy’ students matter?

In their report in the Telegraph, @Josiensor and Rosa Silverman discuss implications of a survey from Cambridge which notes that so-called 'smart' drugs continue to be used by students to try to improve their academic performance, with methylphenidate (Ritalin) a common choice.

Why should this be of public interest?

Methylphenidate has been in use since 1960 for treating ADHD, with effects mainly considered to be improvement in attention and concentration. It is used to treat a number of rare syndromes involving abnormalities in chemical transmission in the brain. The drug is also reported to be in widespread use by students in the UK, the US and elsewhere in the hope that it will improve studying, learning and exam performance.
 

1.    Does it work? Studies of possible effects on studying and learning are typically short-term and usually based on artificial tests – ie not usually test possible benefits of the drug what students may be trying to learn, or effects on the types of exams students may be sitting. Evidence compared to placebo of benefits or risks appears limited to studies lasting 4 weeks or less.

The evidence of benefits from methylphenidate in apparently healthy students is disappointing. For example, in a study in health young volunteers there was a reported benefit from the 1^st dose for a spatial (3D) task and for planning, but not for attention or fluency. However even these effects were not sustained: with a second dose, spatial task performance was less good; ie there was little evidence of sustained benefit on repeat use of the drug and possible evidence that performance might be worse. And one of the side effects is insomnia – fatigue could also therefore be an indirect reason why performance might be impaired by the drug. There are also reports by users that with the drug, too much focus on details may make it difficult both to complete an assessment and to consider a broad enough range of issues to give a complete answer.

2.    Is use of methylphenidate any different from using caffeine? Because of the lack of convincing evidence of benefit from methylphenidate and concerns about serious risks, methylphenidate is not approved for use in the absence of specified medical conditions – e.g. ADHD. As for other drugs, the balance between risk and benefit must be considered by prescriber and user. In the event of any benefit for studying from the drug, others not using it are put at a disadvantage. In contrast caffeine is widely available for those who chose to use it. Too much caffeine, or sensitivity to caffeine can cause troublesome symptoms, including anxiety, tremor, sleep disturbance and palpitations. 

3.    Risks of methylphenidate Potential risks may be serious and include serious cardiac and psychiatric disorders. This has lead to important restrictions by regulatory authorities such as the FDA on use of the drug, even when the drug is medically indicated. 

Withdrawal symptoms of methylphenidate can include psychosis, depression and irritability.

Risks of the drug may be greater if there are medical problems, in particular if the user has a medical history of cardiovascular or psychiatric problems. Use without clinical advice may mean that important underlying conditions are not identified, for example high blood pressure, disorders of heart rhythm, and psychiatric risk; and potential important interactions with other drugs (including other stimulants) may not be considered. For example: 

-      alcohol can delay clearance of the drug from the body, increasing risk of adverse effects; 

-      concurrent use of stimulants such as caffeine would be expected to increase risk from methylphenidate of serious disorders of heart rhythm.

4.    What about access to the drug from internet pharmacies? For the above reasons, licensed pharmacies would not supply methylphenidate in the absence of specified medical conditions. Unlicensed internet pharmacies should be avoided. The quality of medicines is not reliable, with serious risk of being supplied poorly active or counterfeit or contaminated medicines. And medical contra-indications need to be identified and discussed to minimize the risk of preventable serious adverse effects.

5.    Fairness and coercion There are also a number of ethical concerns including:

a)    the need to protect students and others from using so-called ‘smart drugs’ in response to pressure to compete, both in exams and in professional life; 

b)    being fair to other students who do not have access to the drug, or do not wish to use what may be a medically harmful pharmacological aid to improving performance in examinations or to meeting challenges at work.

See also
June 2009: Opposing opinions in the British Medical Journal from John Harris and Anjan Chatterjee

September 2011: Methylphenidate and delayed puberty
July 2012: Methylphenidate for Parkinson's disease
November 2012: Commentary in the Guardian by William Leith: Ritalin before an exam fails the test of common sense 
June 2013: Cautionary report in from Canada on methylphenidate use and learning in  ADHD

Moving the new Personalized Medicine to the Clinic

I am on the Advisory Board for a conference to be held 13-14 May in San Francisco on Personalized Medicine from the perspectives of regulators, biotech and pharma interest, health service funders and patient users of new and emerging technologies in this area.

Trusted doctor-patient relationships form a long recognized key underpinning basis for ensuring as effective as possible disease prevention and treatment. That relationship needs to be supported by a strong evidence base on clinical and cost-effectiveness and safety in use of medicines and supporting diagnostics and devices.

Thanks to economies arising from progress in gene technology (Moore's Law applied to medicine) and advances for exponential increase in active partners in this field (Metcalfe's Law applied to medicine), costs of genetic, genomic and other technologies to stratify diagnosis and treatment choice are becoming increasingly affordable in clinical practice.

The Summit is a one-day conference that will gather biotechnology and pharmaceutical experts and healthcare stakeholders as keynote speakers and panel discussants on legal, regulatory, funding and other key issues that will promote research and development, growth and effectiveness  in the short to medium term horizon for emergence of personalized medicine for clinical care.

The summit is co-hosted by the Personalized Medicine Coalition and Foley & Lardner LLP and is supported by major academic, clinical and industry patrons Life Technologies, Cancer Treatment Centers of America and the California Institute of Regenerative Medicine.

See the Personalized Medicine Summit website for more on the conference and how to register.

Selected papers from the conference will be published in the international journal Health Policy and Technology.

Progress on Personalized Medicine? Updates from Harvard.

@HealthMed The 8th annual Personalized Medicine Conference took place at Harvard this week - a joint venture of Harvard Medical School, Harvard Business School and Partners Healthcare, lead by Professor Raju Kucherlapati, from the HMS Department of Genetics. Worth checking the excellent archive of past programmes, presentations and podcasts.
Meantime, some of the highlights?
- An excellent narrative on the partnership between Plexxikon (Peter Hirth) and Roche Diagnostics (Suzanne Cheng) to create a companion diagnostic/therapeutic pairing for vemurafenib (Zelboraf), the first FDA approved pairing for BRAF V600E positive metastatic melanoma
- Further case studies illustrating successful drug development using genetic approaches
- Personal case studies on the impact, clinical value and ethical and clinical challenges of genomic screening: from Joe Beery, Life Technologies, on detecting unrecognised treatable serious early childhood disorders, to John Lauerman, Bloomberg News, on consequences of sequencing for asymptomatic adults - questions on penetrance and future screening for onset e.g.  of metabolic disease and cancers

Harvard Medical School: New Research Building - Avenue Pasteur.

- Clinical potential, and regulatory and reimbursement challenges to introducing molecular diagnostics into clinical care pathways
- Leadership award to Randy Scott, In Vitae, whose discussion points included the relevance of Moore's Law (technology advancing) and Metcalfe's Law (people factors: exponential increase in interaction as network expands) to developments in personalized medicine
- Business models and their governance for use of genetic information
- A North Virginia (John Vockley, Inova) pioneering series of projects aiming to assess outcomes of neonatal genomic sequencing: from insight into preterm labour to prospective longitudinal follow-up to adulthood, supported by multi-generation family member sequencing combined with clinical histories
- The US Air Force Programme on Patient-Centered Precision Care (Dr Cecili Sessions), in partnership with the Coriell Institute and Johns Hopkins University,  aims of which include understanding the impact on health-related behaviour of providing personal genetic information on remediable medical disorders and on drug responses.
- A business school case study led by Professor Richard Hamermesh, Director of the HBS HealthCare Initiative, on reactive and proactive responses for development of companion diagnostics (1).
- Pros and cons of liberal vs. restrictive approaches to IP for genetic and other molecular diagnostics
- Engaging the policy community and the public in ethical, clinical, reimbursement and adoption issues for new diagnostics and treatments aimed at personalizing medicine, including case studies from the American Medical Association and the American Assocation for Cancer Research.

Personalized Medicine Conference website 
Companion and coupled diagnostics

News of the 2013 EACPT Congress in Geneva

@HealthMed The EACPT's next biennial congress will be held in beautiful Geneva, 28th - 31st August in 2013 at the International Congress Centre of Geneva (CICG).

Registration will open 10^th November 2012.
Abstract submissions will also open 10^th November 2012 and will close 8^th February 2013.

To receive updates on the congress before registering, you can submit your email address to the congress organisers.
Over 900 participants are expected to attend including health professionals, scientists, policy makers, biotechnology and pharmaceutical professionals and others interested in basic and clinical pharmacology, pharmacotherapy, drug discovery and development, regulatory affairs and related areas.

Geneva by the lake

Key themes at the congress will range from bedside pharmacology for special patient groups to pharmacology & toxicology, and pharmacology and society. Specific topics will include sessions on communicating with the public, ethics, safe prescribing, clinical trial design and governance, and health policy; new biologicals, translational medicine and pharmacogenetics; advances in personalised diagnostics to improve the safety and effectiveness of medicines, updates on new biological approaches to ocular disease, therapeutics of cardiovascular, cancer and inflammatory disease, clinical trial design and regulation, and drug safety and toxicology. 

The European Association for Clinical Pharmacology and Therapeutics (EACPT) has its origins in a working party in the early 1980s under the auspices of the World Health Organisation (WHO-Europe). The EACPT's next biennial congresses after Geneva 2013 are in Madrid 2015 and in Prague 2017. The EACPT also arranges summer schools, and other scientific and professional activities.

For more on the Congress, how to contact the organisers, and how to register to receive updates, see:

Congress Website: http://www.eacpt2013.org

Secretariat email: eacptreg@mci-group.com

FPM to launch a new journal on Health Policy and Technology

@HealthMed Health Policy and Technology (HPT), the new official journal of the Fellowship of Postgraduate Medicine (FPM), will be launched in March 2012 as a cross-disciplinary journal, which will focus on past, present and future health policy and the role of technology in clinical and non-clinical national and international health environments. HPT will be published by Elsevier, a major international publisher of scientific, technical and medical information

The FPM continues to publish its first international publication, the Postgraduate Medical Journal, launched in 1925. HPT provides a further excellent way for the FPM to continue to make important national and international contributions to development of policy and practice within medicine and related disciplines. The aim of the FPM in establishing this new international journal is to publish relevant, timely and accessible articles and commentaries to support policy-makers, health professionals, health technology providers, patient groups and academia interested in health policy and technology.

Topics covered  by HPT will include
- Health technology, including drug discovery, diagnostics, medicines, devices, therapeutic delivery and eHealth systems
- Cross-national comparisons on health policy using evidence-based approaches
- National studies on health policy to determine the outcomes of technology-driven initiatives
- Cross-border eHealth including health tourism
- The digital divide in mobility, access and affordability of healthcare
- Health technology assessment (HTA) methods and tools for evaluating the effectiveness of clinical and non-clinical health technologies
- Health and eHealth indicators and benchmarks (measure/metrics) for understanding the adoption and diffusion of health technologies
- Health and eHealth models and frameworks to support policy-makers and other stakeholders in decision-making
- Stakeholder engagement with health technologies (clinical and patient/citizen buy-in)
- Regulation and health economics

Professor Wendy Currie will lead the journal as its founding Editor-in-Chief. Her research, consultancy and publications focus on policy-making for large-scale information and communications technology (ICT) projects in health, financial services and government.

The first issue of Health Policy and Technology will focus on Electronic Health Records in the 21st Century, with papers discussing implementation targets for EHRs in healthcare organizations, cross-border policies for EHRs, financial and non-financial costs of introducing EHRs, clinical and patient engagement with EHRs, government policy for EHRs and country comparisons, security and governance practices in relation to EHRs, and the role of EHRs in campaigns to improve citizens' health and reduce health inequalities.

The first issue also includes a paper on the pioneering new Centre for Health Technology Assessment of Devices and Diagnostics within the UK’s National Institute for Health and Clinical Excellence (NICE). There is also the first of a series of interviews with international leaders in the field of health policy and technology, beginning with Sir Michael Rawlins, Chairman of NICE.

The aim of the Fellowship of Postgraduate Medicine (FPM) is to promote international calibre excellence in postgraduate medical education through its publications, clinical and scientific meetings, and other activities.  The FPM is a British medical charity that was founded at the end of World War I, when it pioneered development of post-graduate educational programmes in all branches of medicine.

Its foundation was the result of a merger between the Fellowship of Medicine and the Postgraduate Medical Association, with Sir William Osler the first president of the new organisation. The FPM is supported by Fellows with expertise in the practice of medicine, medical education and publishing, and research in medicine and related disciplines.

HPT website

FPM website

FPM contact email