Precision medicine in an outdated regulation

Specially dedicated to european politicians, this was my op-ed in Diario Médico last week:

La medicina de precisión en una regulación obsoleta

El retraso regulatorio europeo en pruebas diagnósticas y suministros médicos es descomunal

El avance tecnológico coge por sorpresa a gobiernos y parlamentos. El retraso en actualizar la regulación a las nuevas realidades frena a su vez la difusión de las innovaciones e introduce incertidumbres sobre la eficacia y seguridad. Desde hace más de una década sabemos que el impacto en la asistencia sanitaria de los avances en el genoma humano tendría lugar algún día inexorablemente. Sin embargo,a fecha de hoy, estamos a la espera de su regulación.
En 2005 un periódico anunció que llegaba la medicina personalizada pero muy pronto nos dimos cuenta que todo era más complicado de lo que algunos proclamaban. En 2011, Science decía en portada: “Lo mejor está por venir”. A la secuenciación del genoma humano le faltaba todavía mucho trayecto para que se concretara en impacto en la salud poblacional. Y en el mismo año se publicó el informe del National Research Council estadounidense: “Toward Precision Medicine”. En él se mostraba el impacto del conocimiento biomédico en la clasificación de la enfermedad, describía el reto de la redefinición de la enfermedad a partir de la biología molecular, a la vez que popularizaba el nuevo término: Medicina de Precisión.
En marzo de 2012, Cell publica un artículo crucial donde se relata la aparición molecular de una enfermedad. Un profesor de Stanford relata la evolución de su perfil ómico personal, analiza qué ocurre durante dos años, cómo surge la enfermedad y cuál es la reacción molecular del cuerpo. Explica cómo descubre el riesgo de diabetes y cuando se confirma, qué hace a partir de aquel momento.
Del titular del periódico de hace una década nos acercamos, ahora sí, a la medicina de precisión, intensiva en datos. Las inversiones públicas en iniciativas de investigación son tan solo una parte del todo. Lo que llamábamos “medicina estratificada”, la que une pruebas diagnósticas complementarias (companion diagnostics) para determinar el tratamiento farmacológico, ya está entre nosotros. Ahora es un ejemplo más de medicina de precisión. Y resulta que a fecha de hoy, en Europa tenemos una regulación vigente de 1998 (!). Desde 2012 circula un borrador para actualizar la directiva sin éxito. Recientemente, el pasado 23 de septiembre, ha surgido un nuevo borrador que la Comisión quiere elevar al Parlamento para su aprobación. Veremos qué sucede en esta ocasión.
El texto considera las pruebas diagnósticas complementarias esenciales para definir aquellos pacientes que son candidatos a un tratamiento específico con un medicamento, a través de la determinación cuantitativa o cualitativa de marcadores específicos que identifican los sujetos con mayor riesgo de desarrollar reacción adversa al medicamento o la identificación de los pacientes en la población para los que el producto terapéutico se ha estudiado de manera adecuada, y es seguro y efectivo. La forma como se evalúa la seguridad y eficacia queda al margen de los procesos equivalentes en los medicamentos y se mantienen las entidades certificadoras, si bien con cierto control adicional. Y la pregunta es la de siempre: ‘Quis custodiet ipsos custodes?’, ¿quien vigila al vigilante?. Este “cierto” control gubernamental será suficiente? O quizás cada estado lo resolverá a su propio estilo?.
El sistema europeo basado en la autoregulación, en entidades certificadoras privadas, queda lejos del sistema norteamericano donde las pruebas diagnósticas complementarias se regulan públicamente por la FDA. De esta forma, un medicamento que requiere una prueba diagnóstica queda regulado en Europa en dos ámbitos distintos, con requisitos de evaluación desiguales. En definitiva, estamos a las puertas de una regulación que es incapaz de tener en consideración que la validez y utilidad clínica en la medicina de precisión debe ser objeto de regulación pública directa.
El retraso regulatorio europeo en pruebas diagnósticas y suministros médicos es descomunal. A fecha de hoy se sigue un proceso para acceder al mercado que requeriría una revisión profunda de su impacto en términos de validez y utilidad clínica. La credibilidad de la evaluación se confirma siempre que existan criterios objetivos, fiables y homogéneos. Los mecanismos actuales de certificación son insuficientes para los objetivos que se esperan de una regulación avanzada. Del mismo modo que el escándalo de los implantes mamarios PIP recordaron la falta de garantía y control en suministros médicos, las pruebas diagnósticas requieren una regulación fiable que garantice seguridad y calidad, al mismo tiempo que aporte información sobre su efectividad. No hay opción para más demora. La nueva propuesta de regulación de pruebas diagnósticas necesita una mejora inmediata o, de otro modo, se convertirá en obsoleta a corto plazo.

 

Mapfre Foundation. Barcelona exhibition.

Disentangling ageing and health

World report on Ageing and Health

Although it may surprise, there is no clear pattern to indicate that elderly people  always utilise more health services. When one looks at the aggregated indicators, one may reach this conclusion, however taking into account the realities and individual characteristics, there are many remaining factors to explain the situation. This fact is evidenced by the last WHO report on aging and health. (P.90).
Even considering the increased morbidity at older ages, the burden of chronic diseases is diverse in terms of cost. Thus, few users and its distribution in the phase prior to death, it is the main cause of the high cost of chronic disease. Proximity to death and corresponding therapeutic effort confound the ageing factor in increasing health costs.
Furthermore, it has been shown that the compression of morbidity continues to advance. That is, the occurrence of chronic diseases is delayed gradually, the phenomenon of "survival of the fittest" is confirmed. The impact or impairment of chronic disease in human physiology for the very old is attenuated .
It is for these reasons that the report is worth, a new look to a reality that is already upon us and we need to give appropriate response.

A cause and consequence of progress (again)

Today I would like to suggest you check my previous posts on Angus Deaton, the economics Nobel prize winner. And if you have more time, a close reading of his book is required: The Great Escape: Health, Wealth, and the Origins of Inequality.
Angus Deaton deserves the prize -NYT dixit-. John Cassidy writes an excellent op-ed (The New Yorker) with the title: Angus Deaton: A Skeptical Optimist Wins the Economics Nobel. Nothing to add.

Using behavioral insights for policy

Social and Behavioral Sciences Team 2015 Annual Report

Some weeks ago, an executive order by President Obama boosted the application of behavioral insights to policy.

To more fully realize the benefits of behavioral insights and deliver better results at a lower cost for the American people, the Federal Government should design its policies and programs to reflect our best understanding of how people engage with, participate in, use, and respond to those policies and programs. By improving the effectiveness and efficiency of Government, behavioral science insights can support a range of national priorities, including helping workers to find better jobs; enabling Americans to lead longer, healthier lives; improving access to educational opportunities and support for success in school; and accelerating the transition to a low-carbon economy.

Sounds interesting. It poses a tweak on the current approaches to policy design. Cass Sunstein says in NYT:

 When government programs fail, it is often because public officials are clueless about how human beings think and act. Federal, state and local governments make it far too hard for small businesses, developers, farmers, veterans and poor people to get permits, licenses, training and economic assistance.

 Behavioral research shows that efforts at simplification, or slight variations in wording, can make all the difference.

The UK and now the USA are introducing this new way to define policies (and health policy). Let's keep an eye on its application and performance. What are we doing in this respect? Why are we waiting to introduce something similar?


 President Barack Obama speaks with members of the Social and Behavioral Sciences Team in the Oval Office in January 2015.

Cost-effectiveness of public health interventions

The case for investing in public health

The evidence shows that a wide range of preventive  approaches are cost-effective, including interventions that address the environmental and social determinants of health, build resilience and promote healthy behaviours, as well as vaccination and screening. The evidence in this report shows that prevention is cost-effective in both the short and longer term. In addition, investing in públic health generates cost-effective health outcomes and can contribute to wider sustainability, with economic, social and environmental benefits.

Cost-effectiveness studies  are usually focused towards treatments. This report shows some examples related to public health. Unfortunately,  this is not so common. Up to now my reference on this tòpic was this article. Now I'm adding this report by WHO Euro. And the question remains: if these interventions are so cost-effective, why are we waiting for their implementation?

It is recognized that a comprehensive strategy needs to include a combination of population and targeted individual preventive approaches, but it should be noted that, on average, individual-level approaches were found to cost five times more than interventions at the population level (WHO, 2011a). In general, evidence also shows that investing in upstream population-based prevention is more effective at reducing Health inequalities than more downstream prevention (Orton et al., 2011). Meanwhile, the National Institute for Health and Care Excellence in the United Kingdom found thatmany public health interventions were a lot more cost-effective than clinical interventions (using cost per QALY), and many were even cost-saving (Kelly, 2012).

The healthcare funding conundrum (once again) (2)

Fiscal Sustainability of Health Systems. Bridging Health and Finance Perspectives

Sustainability defined by OECD (p.25):

The OECD defines fiscal sustainability as the ability of a government to maintain public finances at a credible and serviceable position over the long term (OECD, 2013). Fiscal sustainability implies governments are able to maintain policies and expenditure into the future, without major adjustments and excessive debt burdens for future generations. The term refers to overall government spending, revenues, assets and liabilities that reflect past commitments and adapt to future trends such as socio-economic trends and environmental factors.

For the health sector, fiscal sustainability is perhaps best understood as a constraint that needs to be respected, rather than an objective in itself (Thomson et al., 2009). This implies that how governments achieve fiscal sustainability matters, rather than it  becoming a simple cost-cutting exercise.

Of course!. Sometimes OECD writes obvious statements. There is a budget constraint! Perhaps someone has forgotten it.
I understand that in some countries the budget is not credible, because its health basket is more generous and prices are higher compared to the available resources. Is  this a reason to complain about cutbacks?. If there is a budget, the role of any politician is to comply with the budgetary constraint, they must prioritise. Health care is not an excuse to surpass the budget and responsible citizens and parties should acknowledge it.

The healthcare funding conundrum (once again)

Fiscal Sustainability of Health Systems. Bridging Health and Finance Perspectives

Forget economic forecasts, most of them have failed many times. You don't need to be precise about the size of the GDP devoted to health in 2030, it will definitely be more expenses than now. The OECD tries in a new report to review these forecasts and to spread fear in the near future. I think that our societies before the great recession, were able to manage to some extent fiscal deficits. Now it is different, the size of the deficit for future generations is unacceptable.
The report reviews former approaches to supply side and demand side measures for cost-containment. A well known story on the macro-prescription for governments.  My view is not reflected in the document. I have highlighted many times the importance of organizational change, the micro-perspective, i.e. the changes in the structure of incentives and coordination mechanisms in the health system.
This is the most challenging effort for any government, because organizational change and prioritisation represents an attempt to modify the current status quo. Governments are affraid of it, but in my opinion somebody has to handle this conundrum and tell  the population exactly that unless we change current health care organizations, taxes will not be sufficient to pay the bill. Then two options will be open to us: out of pocket or no access. This is the message that this report is unable to explain clearly and now it's time for somebody to disseminate it.

PS. Read the Fiscal Sustainability of Health Systems: Policy Brief 

Measuring population health

Morbilidad, utilización de recursos y costes sanitarios en la comarca del Baix Empordà

In this blog I've explained many times that if I had to pick one health system as a benchmark I would say that it is  Serveis Sanitaris Integrats del Baix Empordà (SSIBE). This is my choice. I've been contributing over the last decade to understand what has happened to the morbidity, utilization and costs of this population.
Now, you have all this research effort in a PhD Dissertation by J. M. Inoriza, a must read. I strongly recommend you to have a look at it. Congratulations to all contributors.

Health policy: what works?

Successes and Failures of Health Policy in Europe. Four decades of divergent trends and converging challenges

Three questions to answer:

• Do differences in rates of disease reflect differences in related policies?
• What would a country gain if it implemented the policies of the best performing country?
• Which social, economic and political factors influence a country's success in health policy?

And the (partial) answer is in chapter 14 of the book:

Gains in health since 1970 for the causes analysed in this chapter have clearly been enormous. While not all of these declines can be attributed to health policies, part of the decline in all these causes can  be, as shown in the previous chapters. For example, some of the declines in lung cancer and  ischaemic heart disease can be attributed to tobacco control; some of the declines in external cause mortality among children to injury prevention, and some of the declines in death rate from RTIs to road safety measures, and so on. It is impossible to estimate the specific contribution of preventive health policies to these declines, but even if these accounted for only half or a quarter of the cause-specifi c declines, the successes would be immense. At the same time, not all countries have been  equally successful in bringing down mortality from these preventable causes, as shown again by the calculations.

The book was released in 2013 with data from 5 years before, an update would be necessary. Anyway, a close reading is required.

The modeling approach to health decisions

Applying Modeling to Improve Health and Economic Policy Decisions in the Americas: The Case of Noncommunicable Diseases

On the role of modeling in health, this OECD report says:

In the health sector, the purpose of modeling is to structure evidence on clinical and economic outcomes in a form that can inform decisions about clinical practices and health care resource allocations. Models synthesize evidence on health consequences and costs from many different sources, including clinical trials, observational studies, insurance claim databases, case registries, public health statistics, and preference surveys. A model’s logical, mathematical framework permits the integration of facts and values and links these data to outcomes that are of interest to health care decisionmakers

I agree. The report shows some examples of aggregated modeling without panel microdata. If you compare this approach with David Eddy one, Archimedes models, it is exactly the opposite. And my opinion is in favour of Archimedes, as you can check in my previous posts. The most useful approach to modeling is the one that allows improve decisions at micro level, physician and patient.

PS. An innovative approach with practical implications in SSIBE, Palamós.

 Bonnard exhibition in Madrid.

The size of income inequality (2)

Source: World Economic Forum: Inclusive Growth and Development Report 2015

Epigenetics contribution to clarify disease mechanisms

Epigenetics at the Crossroads of Genes and the Environment

You may find an updated definition of epigenetics in this JAMA article:

 Epigenetics refers to information transmitted during cell division other than the DNA sequence per se, and it is the language that distinguishes stem cells from
somatic cells, one organ from another, and even identical twins from each other. Examples include (1) DNA methylation, a covalent modification of the nucleotide cytosine, that is copied during cell division at CpG dinucleotides by the maintenance enzyme DNA methyltransferase I; (2) posttranslational modifications of nucleosome proteins about which the DNA double helix is wrapped; and (3) the density of  nucleosomes and higher-order packaging of chromatin within the nucleus, including its relationship to the nuclear lamina.

If this is so, why is the message of predictive genetics so widespread?. I've insisted on this issue before.

 The field of epigenetics and epigenetic epidemiology have much to do to improve measurement of epigenetic marks, inform natural variation in such marks, and the biological and population level relationships between genes, environment, and epigenetics. This is an important emerging area as it holds promise for better risk prediction in precision medicine as well as for clarification of disease mechanisms among the existing opaque landscape only partially informed by traditional genetic and environmental studies to date.

 A short and relevant article that provides hints for further reading.

PS. Epigenetic phenomena, from Nature.

Ownership and access to medical data

Unpatients—why patients should own their medical data

Eric Topol says in Nature Biotechnology:

Today, in the United States, health data live in a plethora of places, from electronic health record (EHR) systems, insurance claims databases, siloed personal health apps, research and clinical trial databases, imaging files and lots of paper. Although seemingly everywhere, any true semblance of an overarching organization or standardization of medical data are lacking, whether at the individual or societal level

His proposal is straightfoward: the ownership of the clinical record is of the patient. This situation is completely different in our country. We have public centralised repositories and the patient is the owner. There is still a lack of coordination and many things to solve, however the basics are covered in the publicly funded System, that's not the case in the private sector.

In contrast to the legal and technical difficulty an individual faces to obtain all his or her own medical data is the relative ease with which hackers have managed to breach ~100 million patient records in the first half of 2015

And his proposal:

 We must begin talking about creating a health data resource in a much broader and more universal context, controlled by the individuals who supply the data. This is a unique moment where we may be able to provide for personal control and, at the same time, create a global knowledge medical resource.

Sounds interesting, though methodology is crucial for success.


PS. Hacking electronic records:

The timeline for electronic medical data hacks in the United States of over 1 million individuals

Cardiovascular disease and diabetes: progress and prospects

OECD Health Policy Studies Cardiovascular Disease and Diabetes

A recent OECD report highlights the huge improvement on cardiovascular disease and at the same time explains the policies and strategies needed for the near future. Treatment improvement accounts for 40% in the decrease of mortality, change in risk factors 50%, while 10% is unexplained. This means that public policy is critical for success. Nowadays it is still the first disease to tackle. On diabetes, the report explains that 85 million europeans are currently suffering from the disease. Therefore, it remains a severe issue.
I suggest you take a close look at the report.