Vaccine nationalism

 The Optimal Allocation of Covid-19 Vaccines

Covid-19 vaccine prioritization is key if the initial supply of the vaccine is limited. A consensus is emerging to first prioritize populations facing a high risk of severe illness in high-exposure occupations. The challenge is assigning priorities next among high-risk populations in low-exposure occupations and those that are young and healthy but work in high-exposure occupations. We estimate occupation-based infection risks and use age-based infection fatality rates in a model to assign priorities over populations with different occupations and ages. Among others, we find that 50-year-old food-processing workers and 60-year-old financial advisors are equally prioritized. Our model suggests a vaccine distribution that emphasizes age-based mortality risk more than occupation-based exposure risk.

Today we can confirm that the probability of such proposal is low. After reading FT, WHO framework has suffered a setback.

Banksy

Forming beliefs

The Value of Beliefs

Relevant article with key messages:

We construct our beliefs to meet two sometimes conflicting goals: forming accurate beliefs to inform our decisions and forming desirable beliefs that we value for their own sake. In this NeuroView, we consider emerging neuroscience evidence on how the brain motivates itself to form particular beliefs and why it does so.

Our beliefs are fundamental parts of what makes each of us unique. They are a major cause of both harmony and discord; shared beliefs bring people together, while divergent beliefs can spark revolutions. In this age of the internet and social media, the ability of beliefs to both invigorate and polarize is more apparent than ever. This raises a fundamental question: how do people arrive at their beliefs? A traditional approach to studying beliefs is grounded on the idea that people build an internal model of the world for the purpose of informing their decisions to help them achieve external goals, such as gaining rewards and avoiding punishments.

 In particular, individuals often prefer to hold positive beliefs and hold beliefs with high certainty. To achieve this, changes in information seeking and belief updating are motivated by tapping into the same circuits that drive primary reward seeking. However, unlike primary rewards such as food, beliefs on their own do not directly promote survival.

How advances in biological science are transforming economies and societies

The Bio Revolution: Innovations transforming economies, societies, and our lives

McKinsey Global Institute is well known by their excellent papers and analysis. Forget consultancy for a while, if you are interested in the disruptive knowledge, go to MGI. Recently they have released an excellent report on the Bio Revolution. This is a timely contribution for an issue that those that read this blog already know: we are within a huge change on how life has been considered. CRISPR technology, among others, are changing quickly the landscape.

The potential scope and scale of the (direct and indirect) impact of biological innovations appear very substantial. As much as 60 percent of the physical inputs to the global economy could be produced biologically. Around one-third of these inputs are biological materials (such as wood). The remaining two-thirds are not biological materials, but could, in principle, be produced using innovative biological processes (for instance, bioplastics).

A pipeline of about 400 use cases, almost all scientifically feasible today, is already visible. These applications alone could have direct economic impact of up to $4 trillion a year over the next ten to 20 years. More than half of this direct impact could be outside human health in domains such as agriculture and food, consumer products and services, and materials and energy production. Taking into account potential knock-on effects, new applications yet to emerge, and additional scientific breakthroughs, the full potential could be far larger.

A must read.

Climate change and health

Enviromedics: The Impact of Climate Change on Human Health

These are tough times for the relationship between mankind and the planet. Therefore, this is a good reason to know better the relationship between climate change and health. In this book you'll find the details on each topic.
These are the key issues:

Part I. Climate Change Cascade
2 Climate Change 101: A Primer
3 Heat Waves and Heat Stress
4 Extreme Weather
5 Vector-Borne Diseases
6 Mental Health
Part II. Clear and Present Pathogens
7 Air Degradation
8 Water Security
9 Food Security
10 Allergens
11 Harmful Algal Blooms 

 Many of these modern sources of environmental hazards share a common feature—they derive from human activity as much as or more than from nonhuman sources. Radiation exists in nature, but its concentrated forms on Earth are created by humans. Industries produce the goods that support modern life, while they spin off by-products that can harm the environment and humans. We celebrate the productivity of modern agriculture, but if the runoff of pesticides and antibiotics pollutes the water supply and encourages antimicrobial resistance, we pay a higher price than we realize for food.

Balancing this tradeoff is complicated by the fact that the individuals and interests who typically stand to benefit from a polluting activity are not the same as the ones who will suffer the adverse health and other consequences.

Global externalities and how to fix them. This is one of the greatest challenges nowadays.

The world is fat

 The Heavy Burden of Obesity – The Economics of Prevention

Almost a decade after the publication of the first OECD report on obesity, a new one has been released. This are the facts:

More than half the population is now overweight in 34 out of 36 OECD countries and almost one in four people is obese. Average rates of adult obesity in OECD countries have increased from 21% in 2010 to 24% in 2016, so an additional 50 million people are now obese. Despite a drive in the last decade to deal with increased obesity, more needs to be done amid sedentary lifestyles and an almost 20% increase in calorie supply – i.e. calories available for consumption – in the OECD over the past 50 years.

So what?

The OECD identifies four categories of policies to tackle the problem and gauges the effect of three promising “policy packages” to help countries achieve greater impact and coherence in tackling the obesity epidemic. Food and menu labelling, regulation of advertising of unhealthy foods to children and the promotion of exercise, including by doctors and schools, are among the measures analysed.

Most of the strategies requires a confrontation with the food industry, and governments usually try to avoid it. We'll see what happens.

Medicine as a data science (6)

Adapting to Artificial Intelligence: Radiologists and Pathologists as Information Specialists

While some physicians are lobbying for creating more specialties, Jah and Topol argue exactly the opposite. Radiology, pathology and in vitro diagnostics should be under the same umbrella: "the information specialists":

Because pathology and radiology have a similar past and a common destiny,
perhaps these specialties should be mergedinto a single entity, the “information specialist,” whose responsibility will not be so much to extract information from images and histology but to manage the information extracted by artificial intelligence in the clinical context of the patient.

 There may be resistance to merging 2 distinct medical specialties, each of which has unique pedagogy, tradition, accreditation,and reimbursement.However, artificial intelligence will change these diagnostic fields. The merger is a natural fusion of human talent and artificial intelligence. United, radiologists and pathologists can thrive with the rise of artificial intelligence. 

The history of automation in the broader economy has a reassuring message. Jobs are not lost; rather, roles are redefined; humans are displaced to tasks needing a human element. Radiologists and pathologists need not fear artificial intelligence but rather must adapt incrementally to artificial intelligence, retaining their own services for cognitively challenging tasks.A unified discipline, information specialists would best be able to captain artificial intelligence and guide medical information to improve patient care.

You may agree or not. Technology is breaking barriers and creating bridges. Food for thought.

Josep Segú - Brooklyn Bridge

Exhibition at Sala Parés

Times of resistance

When All Else Fails: THE ETHICS OF RESISTANCE TO STATE INJUSTICE

The economist Albert O. Hirschman famously argued that citizens of democracies have only three possible responses to injustice or wrongdoing by their governments: we may leave, complain, or comply. But in When All Else Fails, Jason Brennan argues that there is a fourth option. When governments violate our rights, we may resist. We may even have a moral duty to do so.
For centuries, almost everyone has believed that we must allow the government and its representatives to act without interference, no matter how they behave. We may complain, protest, sue, or vote officials out, but we can’t fight back. But Brennan makes the case that we have no duty to allow the state or its agents to commit injustice. We have every right to react with acts of “uncivil disobedience.” We may resist arrest for violation of unjust laws. We may disobey orders, sabotage government property, or reveal classified information. We may deceive ignorant, irrational, or malicious voters. We may even use force in self-defense or to defend others.
The result is a provocative challenge to long-held beliefs about how citizens may respond when government officials behave unjustly or abuse their power.

Food for thought.

Docuncert Txarango 

Research and results

The Biomedical Bubble: Why UK research and innovation needs a greater diversity of priorities, politics, places and people

More resources for research are needed. This is the usual mantra. However, what about outcomes?. Since this is not so easy to measure it really lies in an uncertain land. A new report tries to put things clearer, at least for UK. It explains the mismatch about research funding and what is needed to improve health. This is exactly what I consider the right approach. It is useless to ask for more money unless we explain and focus on the priorities for achieveing better health.

A biomedical bubble has developed, which threatens to unbalance the UK’s research and
innovation system, by crowding out the space and funding for alternative priorities. This
is not a speculative bubble, as developed for tulips in the 1630s, or dotcoms in the early
2000s; there is far too much substance in the biomedical sciences for this. But it is a social, political and epistemic bubble (similar to the ‘Westminster bubble’, or the ‘filter bubble’), in which supporters of biomedical science create reinforcing networks, feedback loops and commitments beyond anything that can be rationalised through cost-benefit analysis.

The biomedical bubble represents a risky bet on the continued success of the pharmaceutical industry, despite mounting evidence that this sector faces a deepening
crisis of R&D productivity, and is cutting its own investment. And it favours a particular approach to the commercialisation of science, based on protectable intellectual property and venture capital based spinouts – despite the evidence that this model rarely works. Our health and social care system is under growing strain, and as the NHS marks its 70th birthday this month, there is renewed debate about its long-term affordability. Too often, the biomedical bubble distracts attention and draws resources away from alternative ways of improving health outcomes. Only 5 per cent of health research funding is spent on researching ways of preventing poor health. And more than half is spent in three cities - London, Oxford and Cambridge - despite variations in life expectancies of up to eight years across the country. This paper argues for a more balanced distribution, aligned to what the evidence clearly shows are crucial social, economic, environmental and behavioural determinants of better health outcomes.

 Food for thought.

Shomei Tomatsu in Barcelona

Public funding of succesful Pharma R&D

Contribution of NIH funding to new drug approvals 2010–2016

If we consider the 210 new molecular entities (NMEs) approved by the Food and Drug Administration from 2010–2016, then you'll find that NIH funding contributed to published research associated with every one. A PNAS article explains that:

Collectively, this research involved 200,000 years of grant funding totaling more than $100 billion. The analysis shows that 90% of this funding represents basic research related to the biological targets for drug action rather than the drugs themselves. The role of NIH funding thus complements industry research and development, which focuses predominantly on applied research. This work underscores the breath and significance
of public investment in the development of new therapeutics and the risk that reduced research funding would slow the pipeline for treating morbid disease.

This public funding is forgotten in the costs of a new molecule. Although in the price, the manufacturer surplus doesn't remunerate such contribution. Some adjustment should be applied, to be fair.

 Brassai at Mapfre Foundation in Barcelona

The apocalypse and our true fate, who knows?

THE FIVE HORSEMEN OF THE MODERN WORLD: Climate, Food, Water, Disease, and Obesity

In the book of Revelation or Apocalypse of John, you'll find the seven bowls. Seven angels are thus given seven bowls of God's wrath, each consisting of judgements full of the wrath of God poured onto Earth:

First Bowl: A "foul and malignant sore" afflicts the followers of the Beast. (16:1–2)
Second Bowl: The Sea turns to blood and everything within it dies. (16:3)
Third Bowl: All fresh water turns to blood. (16:4–7)
Fourth Bowl: The Sun scorches the Earth with intense heat and even burns some people with fire. (16:8–9)
Fifth Bowl: There is total darkness and great pain in the Beast's kingdom. (16:10–11)
Sixth Bowl: The Great River Euphrates is dried up and preparations are made for the kings of the East and the final battle at Armageddon between the forces of good and evil. (16:12–16)
Seventh Bowl: A great earthquake and heavy hailstorm: "every island fled away and the mountains were not found." (16:17–21)

As you may notice Apocalypse is just that, a book. Daniel Callahan set a title of five horsemen of the modern world as a metaphor of current evils. Global warming, food shortages, water shortages and quality, chronic illness, and obesity could be the key ingredients of our fate?.
At the end, Daniel Callahan calls for a diplomatic model:

to persuade the research, academic, and policy communities to accept what I will call the diplomatic model of relationships, typically now seen between and among nations, and to open a serious dialogue with the business community

Agree.

When science and regulation don't talk to each other

An Evidence Framework for Genetic Testing

National Academy of Sciences and Food and Drug Administration don't talk to each other. At the same time that NASEM publishes a report on how to assess genetic testing, FDA clears genetic testing for 23andme without any precise assessment, for the following tests:

• Parkinson’s disease, a nervous system disorder impacting movement
• Late-onset Alzheimer’s disease, a progressive brain disorder that destroys memory and thinking skills
• Celiac disease, a disorder resulting in the inability to digest gluten
• Alpha-1 antitrypsin deficiency, a disorder that raises the risk of lung and liver disease
• Early-onset primary dystonia, a movement disorder involving involuntary muscle contractions and other uncontrolled movements
• Factor XI deficiency, a blood clotting disorder
• Gaucher disease type 1, an organ and tissue disorder
• Glucose-6-Phosphate Dehydrogenase deficiency, also known as G6PD, a red blood cell condition
• Hereditary hemochromatosis, an iron overload disorder
• Hereditary thrombophilia, a blood clot disorder

Meanwhile NASEM recommends a decision framework for the use of genetic tests in clinical care:

1. Define genetic test scenarios on the basis of the clinical setting, the purpose of the test, the population, the outcomes of interest, and comparablealternative methods.
2. For each genetic test scenario, conduct an initial structured assessment to determine whether the test should be covered, denied, or subject to additional evaluation.
3. Conduct or support evidence-based systematic reviews for genetic test scenarios that require additional evaluation.
4. Conduct or support a structured decision process to produce clinical guidance for a genetic test scenario.
5. Publicly share resulting decisions and justification about evaluated genetic test scenarios, and retain decisions in a repository.
6. Implement timely review and revision of decisions on the basis of new data.
7. Identify evidence gaps to be addressed by research.

If you want further details, check Mathew Herper blog. My first impression after reading it is that this move, paves the way for recreational genetic testing. An approach that should be completely banned by legislation. If FDA has done so, let's wait for what it may happen in Europe where the regulator is still planning a change of the regulation in 2022!!! Meanwhile, the door is open (to the worst for citizens).

New album by Txarango. Enjoy it!

How bad health regulation leads to unsafety medical devices in Europe

Comparison of rates of safety issues and reporting of trial outcomes for medical devices approved in the European Unión and United States: cohort study

The topic sould be at the top of health policy agenda (at least as it is in this blog). New evidence confirms the additional safety risks of european bad regulation.

In the European Union, medical devices are approved by private notified bodies if they meet performance criteria and are likely to be safe, but notified bodies generally do not require evidence of effectiveness for most devices. Many high risk devices are approved faster in the EU than in the United States, where the Food and Drug Administration usually requires prospective clinical trials of such devices.

And the results are in BMJ:

The unadjusted rate of safety alerts and recalls for devices approved first in the EU was 27% (62/232) compared with 14% (11/77) for devices approved first in the US. The adjusted hazard ratio for safety alerts and recalls was 2.9 (95% confidence interval 1.4 to 6.2) for devices approved first in the EU.

This means exactly 2.9-fold greater rate of safety alerts and recalls and a 4.6-fold greater rate of recalls than devices approved first in the US  (and if you look at the confidence intervals you'll get more worried).  How can we trust the european regulator?. For decades, European Union has leaved its citizens with less safety protection than is required for medical devices. A perfectly designed absurdity to disseminate risk for european citizens that the new proposed regulation is unable to correct.

PS. If you wnat to understand the differences between EU and US regulation, read this NEJM article or Milbank one..

Food and risk perception

Food and the Risk Society: The Power of Risk Perception

This is the main message of the book: Do not send generic messages on food and its risks, the time for segmentation has arrived,

A generic approach, involving the provision of vast amounts of information to the general public, stands a real risk of leading to information overload, bewilderment and lack of interest among mainstream consumers. A more effective approach to change consumer food buying and consumption behaviour, is to focus on segmenting the population according to their information needs, and developing information with high levels of personal relevance to specific groups of respondents who may be at greater risk than the rest of the population. Such information is more likely to create attitudinal change and subsequent behavioural change as the perceived personal relevance is high.

Is the government already prepared for the task?

Introducing nudging in the law

Nudge and the Law. A European Perspective

Alberto Alemanno is an HEC law professor focused on issues on behavioral policies and regulation. Now he has edited an interesting book. You can check it from this index:

1. The Emergence of Behavioural Policy-Making:A European Perspective

Part I: Integrating Behavioural Sciences into EU Law-Making
2. Behavioural Sciences in Practice: Lessons for EU Rulemakers
3. Nudging and Evidence-Based Policy in Europe: Problems of Normative Legitimacy and Effectiveness
4 . Judge the Nudge: In Search of the Legal Limits of Paternalistic Nudging in the EU

Part II: De-Biasing Through EU Law and Beyond
5. Can Experts be Trusted and what can be done about it? Insights from the Biases and Heuristics Literature
6. Overcoming Illusions of Control: How to Nudge and Teach Regulatory Humility

Part III: The Impact of Behavioural Sciences on EU Policies
7. Behavioural Sciences and EU Data Protection Law: Challenges and Opportunities
8. Behavioural Sciences and the Regulation of Privacy on the Internet
9. EU Consumer Protection and Behavioural Sciences:Revolution or Reform?
10. What can EU Health Law Learn from Behavioural Sciences? The Case of EU Lifestyle Regulation
11. Conduct of Business Rules in EU Financial Services Regulation: Behavioural Rules Devoid of Behavioural Analysis?

Part IV: Problems with Behaviourally Informed Regulation
12 . Making Sense of Nudge-Scepticism: Three Challenges to EU Law ’ s Learning from Behavioural Sciences
13. Behavioural Trade-Offs: Beyond the Land of Nudges Spans the World of Law and Psychology
14. Epilogue: The Legitimacy and Practicability of EU Behavioural Policy-Making

The book deserves time reading it, specially if you are interested in latest trends on nudging and regulation. However, if you don't have enough time, go straight to chapter 10. This is what you should read about implications of nudging on Public Health. He says,

Our previous analysis made a case for more experimentation in behaviourally informed regulation in the EU lifestyle policy. This seems particularly true when examined in light of the limited results attained by self-regulatory schemes led by the food, alcohol, and tobacco industries. While the evidence of what works in terms of behaviour change strategies is limited and too often anecdotal, several success factors have progressively been identified in policy-making.

 These success factors are those we have to check in our close environment and test wether it is worth taking this regulatory approach.

Improving physician compensation

A Guide to Physician-Focused Alternative Payment Models

A fixed flat monthly payment to  physicians is a vulgar method to compensate a professional effort. At some initial stages of the career, it may work. As far as experience and knowledge improves results, than some adjustments are needed. In general the publicly funded health system is not able to change the initial stage and remains with more or less the same approach of low-powered incentives. This may work for some individuals, but not for all of them.
Paying on a fee-for service it creates strong incentives to boost volume, and paves the way to overdiagnosis and overtreatment. Privately funded health care is still using mostly this high-powered approach and it is also not able to reform.
Alternative methods of compensating physicians have been described recently in an interesting report. Forget for a while that it is based on the US health system. These are the seven options:

APM #1: Payment for a High-Value Service 
APM #2: Condition-Based Payment for a Physician’s Services

APM #3: Multi-Physician Bundled Payment

APM #4: Physician-Facility Procedure Bundle

APM #5: Warrantied Payment for Physician Services

APM #6: Episode Payment for a Procedure

APM #7: Condition-Based Payment

Food for thought. Something should done to go beyond fee-for service. And do not forget it, changing incentives without any organizational alignment or reform may drive to surprises and poor performance.

PS. Just the opposite to us, NHS expands private care . A controversial trend.

Inducing methylation

Nutrition, Exercise and Epigenetics: Ageing Interventions

Epigenetics refers to an inheritable but reversible phenomenon that changes gene expression without altering the underlying DNA sequence. Thus, it is a change in phenotype without a change in genotype. The field of epigenetics is quickly growing especially because environmental and lifestyle factors can epigenetically interact with genes and determine an individual’s susceptibility to disease. Interestingly, aging is associated with substantial changes in epigenetic phenomena. Aging induces global DNA hypomethylation and gene-specific DNA hypermethylation due to the altered expression of DNA methyltransferases (DNMTs).

The evidence of the impact of epigenetics on aging is growing. And nutrition plays a key role on epigenetics through the life course. Thus, there are crucial reasons to focus on nutrition early in life.

It is clear that epigenetic alterations caused by aging may provide a milieu that can develop age-associated diseases such as cancer, cardiovascular diseases, neurocognitive diseases and metabolic diseases. Nutrition is one of the most important environmental factors that can modify epigenetic phenomena. Therefore, one might speculate that nutrition may delay the age-associated epigenetic change and possibly reverse the aberrant epigenetic phenomena that can cause age-associated diseases. Indeed, many nutrients and bioactive food components, which can affect one-carbon metabolism that can regulate methylation of DNA and histone or directly inhibit epigenetic modifying enzymes, are showing promising results in delaying the aging process and preventing age-associated diseases through epigenetic mechanisms.

And beyond nutrition, there is exercise. This is what this book explains and it shows the foundations for better health. If it's "only" an issue of regulating methylation...where are the incentives?

Fragmented regulators in globalized markets

Food and Drug Regulation in an Era of Globalized Markets

The complexities of a globalized world have its impact on food and drug regulation. The options for a collaborative space between different agencies are huge, though the interest is low. Its an issue of power and fear, everybody knows that cooperating would be better, but a lack of commitment is the final result. This is not only an issue for health, of course, but I would like to highlight the fact that this should be the first issue of concern by health politicians worlwide. Meanwhile, you can read this book, though it is partial and limited but shows the current situation.

A much-needed start: soda tax

Soda Politics: Taking on Big Soda (and Winning)

Obesity is a top concern on public health. Personal and collective responsibilities are linked. The concrete issue is the following one: government may require manufacturers to release information to consumers (about calories, composition, etc.), but is there anything else that he can do?
Current strategies fall short to achieve the goals of obesity reduction. Nutritional labels are not enough, are taxes an option?. Some countries have already implemented taxes on fizzy drinks, fat or salty foods. There are complex technical issues to be considered. However, The Economist says that taxes on fizzy drinks seems to work as intended. If this is really so, then there is a much-needed reason to start in this way.
Marion Nestle in her latest book "Soda Politics" provides the hole list of arguments. Any regulator should read in detail the book, specially part IX on "Advocacy: Soda caps, taxes and more", and take into account her recommendation:

 Let me acknowledge immediately that advocacy to reduce soda intake faces special challenges that distinguish it from advocacy for reduction of alcohol, tobacco, or junk foods. Like these other industries, the soda industry sells relatively inexpensive products that are available in almost every corner of the globe. Like them, this industry is extremely wealthy. Also like the others, health is the industry’s Achilles’ heel. But in sharp contrast to companies selling junk food, alcohol, or tobacco, Coca-Cola and PepsiCo consistently rank among the most admired, respected, and honored companies in the world. Health and environmental advocates must recognize the power of this favorable public perception when encouraging others to resist it.

PS. A must read. Understanding 25 years of health policy in Catalonia, released in this journal: Referent. You'll find an article that I have written for the occasion.

Lab tests and biomarkers regulation: a pending topic

La regulació de proves diagnòstiques i biomarcadors: una assignatura pendent

Pere Ibern

Centre de Recerca en Economia i Salut. Universitat Pompeu Fabra. Barcelona.

ANNALS DE MEDICINA: VOLUM 98, NÚMERO 4, octubre / novembre / desembre 2015

http://www.acmcb.es/Portal/academia/Publicacions/Annals/Article/_eUM6Y0IFwOjYx8pCJ5Bx15ay5J1m7qc6wEtj4brzgoIIUpHpSJRmF06atHkGpIiX2pkBCC6HLMLzC5Sk3H_dIR1o3PfH30UE

Introducció

A partir de l’any 2010, a Europa va augmentar la preocupació per la seguretat i l’eficàcia dels subministraments mèdics i proves diagnòstiques. Les alertes relatives a la seguretat de les pròtesis mamàries PIP (Poly Implant Prothèse) van ser-ne el detonant. El Parlament europeu va iniciar una revisió de la regulació existent perquè la considerava desfasada i insatisfactòria per assolir els objectius que pretenia. L’any 2012 es van publicar les propostes de nova regulació, però malauradament el cicle electoral no va permetre la seva aprovació. Recentment, el mes de juny de 2015 s’ha publicat la nova proposta que conté múltiples esmenes i tracta d’arribar a un consens definitiu. Si tenim en compte que la regulació actual relativa a proves diagnòstiques és de 1998, i que es proposa un termini de 5 anys per a la seva aplicació, hauran passat efectivament més de vint anys sense adaptar-ne la regulació en un context d’innovació tecnològica accelerada.

La medicina estratificada

La regulació per a protegir la salut dels ciutadans hauria de seguir un procés paral·lel al canvi tecnològic i la innovació, però sabem que es produeixen retards notables en la presa de decisions públiques. Així, per exemple, en aquestes dues darreres dècades hem estat testimonis de l’eclosió de la medicina estratificada¹. Entenem per medicina estratificada aquella que millora els resultats de salut i la capacitat predictiva mitjançant la utilització de biomarcadors. Les condicions necessàries per desenvolupar la medicina estratificada són tres: un mecanisme biològic singular que aporti respostes diferencials dels pacients a la teràpia, unes opcions terapèutiques múltiples que ofereixin respostes heterogènies i un biomarcador clínic que relacioni les teràpies amb una subpoblació de pacients que probablement mostrarà una resposta diferencial. L’aparició de proves diagnòstiques complementàries (companion diagnostics), una de les modalitats de biomarcadors, permet l’estratificació de pacients i la selecció de medicaments i dosi; així augmenta l’eficàcia i es redueixen els efectes adversos.

L’Agència Europea del Medicament (EMA, sigla de l’anglès European Medicines Agency) havia autoritzat fins a 20 medicaments oncològics a principis de 2014 que inclouen un biomarcador farmacogenòmic (Tau1a 1)². L’aplicació acurada de la medicina estratificada té la singularitat de reduir la mida del mercat potencial de la medicina empírica, quan s’administra als pacients que presenten una característica determinada. Aquest fet té implicacions múltiples en relació al preu i el retorn de la investigació, qüestions que ara són de gran actualitat.

TAULA 1. Medicaments oncològics autoritzats per l’Agència Europea del Medicament a principis de 2014 que inclouen un biomarcador farmacogenòmic²

Abreviacions: UE: Unió Europea; DCI: Denominació comuna internacional; ACA: Assaigs clínics aleatoritzats.

La dificultat essencial rau en l’avaluació de les proves diagnòstiques complementàries en la mesura que presenten nous reptes desconeguts fins el moment³. Els tres àmbits on el regulador ha d’oferir resposta són: validesa analítica (la fiabilitat i precisió per detectar la variació genètica d’interès), validesa clínica (fiabilitat i precisió per detectar pacients amb la malaltia d’interès) i utilitat clínica (possibilitat que aporti una millora en la salut). Tradicionalment, l’enfoc de l’avaluació de les proves diagnòstiques ha estat en la validesa analítica; amb la medicina estratificada cal anar més enllà i relacionar-ho conjuntament amb l’opció terapèutica.

Actualment, els biomarcadors són considerats per la regulació europea de diagnòstic in vitro com de baix risc i, per tant, no calen dades d’eficàcia clínica o utilitat clínica per a la seva adopció. A la proposta de nova regulació hi ha un canvi de classificació i es consideren classe C, és a dir, que tenen un risc moderat per a la salut pública o un alt risc individual. En aquests casos, el procediment actual d’autocertificació ja no serà suficient; caldrà aportar informació precisa de validesa analítica i clínica i d’utilitat clínica a les entitats certificadores. El procés de coordinació amb l’EMA encara no està definit i aquesta és una mancança important. Les diferències entre la regulació europea i la dels Estats Units són notables. La Unió Europea ha optat per autoregulació i certificació en l’àmbit privat, amb empreses certificadores, mentre que als Estats Units hi ha regulació directa des de l’àmbit públic. Ara bé, la darrera proposta europea assenyala un nivell d’intervenció superior que implica major control directe sobre les entitats certificadores i sobre els requeriments d’informació. Es trobaria, per tant, a mig camí. Atesa la complexitat dels biomarcadors, la garantia d’aplicació d’un procés d’avaluació homogeni pot quedar en dubte quan no hi ha un organisme central que ho verifica, com és el cas de l’EMA per als medicaments. És llavors quan, a posteriori, les agències d’avaluació de tecnologies previsiblement acabaran tenint un paper clau en aquest àmbit.

L’experiència d’avaluació de tecnologies sanitàries per a les proves diagnòstiques complementàries és encara molt primerenca. L’aplicació de l’anàlisi cost-efectivitat a aquestes proves planteja reptes metodològics nous que han estat descrits per part de l’agència britànica NICE (National Institute for Health and Care Excellence)⁴. La diferència clau sorgeix si la prova diagnòstica s’ha desenvolupat en el marc de l’assaig clínic del medicament o no i, per tant, quin és el seu impacte per estratificar subpoblacions. En aquest sentit, la guia del NICE suggereix avaluar l’impacte diferencial d’una prova diagnòstica complementària en el cost-efectivitat del medicament. El programa d’avaluació de proves diagnòstiques dins el NICE ha anat prenent forma i publica els informes corresponents una vegada els medicament tenen l’autorització de comercialització.

Allò que les agències d’avaluació de tecnologies prendran com a punt de partida són uns biomarcadors que han estat aprovats per ser aplicats conjuntament amb un possible medicament segons la indicació establerta per l’EMA. Però cal tenir en compte que la definició dels punts de tall (cut off) de la prova diagnòstica i aquesta definició la duu a terme el fabricant. En la mesura que la sensibilitat i l’especificitat no siguin del 100%, hi ha proves diagnòstiques que mostraran falsos negatius i falsos positius. És llavors quan la definició del punt de tall té a veure amb la mida del mercat potencial per al medicament. Per exemple, si el punt de tall és alt això comportaria una elevada especificitat i pocs falsos positius i s’obtindrien els millors resultats clínics. Però, alhora, el fabricant obtindria menors ingressos degut al sistema de preus vigents, que no té en compte el valor en salut que aporten els medicaments. Hi ha, per tant, implicacions múltiples de la definició del punt de tall, tant per a pacients com per a empreses, regulador i finançador. Per ara, aquesta decisió recau en les empreses, però caldria avaluar-ne possibles alternatives i que les agències hi tinguessin un paper. Segons Trusheim i Berndt⁵, amb l’actual sistema de preus dels medicaments, l’estratègia preferida per fabricants i pacients seria la d’un punt de tall baix o mitjà —que aporta més tractaments a més pacients i també amb més falsos positius. Però això els portaria a una situació tipus “dilema del presoner”, on cadascú fent el millor per ell mateix acaba obtenint el pitjor resultat, lluny de l’eficiència òptima.

Hi ha almenys dues qüestions diferencials de caràcter regulador en la medicina estratificada: l’avaluació conjunta de medicament i prova diagnòstica complementària i la fixació del preu. Tant la US Food and Drug Administration (FDA) com l’EMA han publicat les seves guies d’avaluació sobre aquest tema, si bé la qüestió dels punts de tall comentada resta pendent de clarificació. De fet, planteja problemes pràctics perquè més enllà d’exigir que la prova diagnòstica s’inclogui a l’assaig clínic —que no passa sempre—, cal també establir diferents escenaris per calibrar millor l’impacte de la sensibilitat i l’especificitat en els resultats en salut.

En relació a les alternatives a la fixació de preus, en certa mesura, els acords de risc compartit serien una opció a tenir en compte si els indicadors fisiològics de la malaltia són clars i unívocs. Sabem que no sempre és així i aquest és el motiu pel qual no es poden dur a terme o que aquells que ho fan acabin essent imperfectes. Les decisions de prioritats terapèutiques de recerca i previsions de facturació a la indústria farmacèutica es fan amb caràcter global. Els preus acaben essent locals; cada país o cada finançador té els seus. L’opció pràctica a considerar és que si es mantenen els preus com a mecanisme i no hi ha o no són possibles contractes de risc compartit, les agències del medicament també haurien de tenir veu a l’hora de decidir el punt de tall que maximitza el valor en salut.

La medicina de precisió

Al llarg d’aquest article s’ha utilitzat el terme medicina estratificada. Recentment, el terme medicina de precisió ha estat objecte de gran ressò per la inversió multimilionària en recerca anunciada pel govern nord-americà. La definició que s’estableix és pròxima: són aquells tractament dirigits a les necessitats de pacients individuals a partir de característiques genètiques, epigenètiques i biomarcadors que els distingeixen d’altres pacients similars. Aquesta definició ens situa més enllà dels biomarcadors farmacogenòmics dels que hem parlat abans.

Ens trobem doncs en un moment de confluència d’aplicació de tecnologies a la medicina que obliga a estar atents a la seva adopció en funció del valor que aporten. La comprensió de la seva complexitat exigeix, a més a més, millor coneixement i formació per part dels diferents actors en el sistema de salut.  Entre ells destacaria també els organismes reguladors. Les proves diagnòstiques són una peça clau d’aquest desenvolupament tecnològic i, a data d’avui, la seva regulació encara és una assignatura pendent de resoldre.

REFERÈNCIES BIBLIOGRÀFIQUES

1. Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov. 2007;6(4):287-93.
2. Pignatti F, Ehmann F, Hemmings R, Jonsson B, Nuebling M, Papaluca-Amati M, et al. Cancer drug development and the evolving regulatory framework for companion diagnostics in the European Union. Clin Cancer Res. 2014;20(6):1458-68.
3. Ibern P. The hole for genetic testing market entry. Bloc Econsalut, 25 de febrer de 2014. Consultable a:http://econsalut.blogspot.com/2014/02/the-hole-for-genetic-testing-market.html. Accés el 9 d’octubre de 2015.
4. Byron SK, Crabb N, George E, Marlow M, Newland A. The health technology assessment of companion diagnostics: experience of NICE. Clin Cancer Res. 2014;20(6):1469-76.
5. Trusheim MR, Berndt ER. An overview of the stratified economics of stratified medicine. Working Paper No. w21233. National Bureau of Economic Research; 2015.

MABS in history of medicine

The Lock and Key of Medicine Monoclonal Antibodies and the Transformation of Healthcare

While reading FT this summer I came across an article quoting a unique book on history of monoclonal antibodies (MABS). Right now there are more than 30 drugs in the market based on hybridoma technology that was created in 1975.
The birth of MABS is explained with full details, how the creators finally didn't patented it and why, the difficulties for research in an unconnected world, etc... An exciting story that is worth reading. Right now, it would be completely different, commercialization of research and medicine has raised considerably.

That a British company spearheaded the first marketing of Mabs, a technology devised in a British laboratory by an émigré Argentinian scientist with his German colleague, highlights the international nature of biotechnology commercialization. Sera- Lab’s venture to sell Mabs took place in the midst of the excitement generated by the founding of Genentech in 1976. The emergence of Genentech, which had been set up
to market recombinant DNA products, galvanized numerous alliances among academics, entrepreneurs, and venture capitalists to launch new companies to commercialize biotechnology. Most of the early enterprises set up in the wake of Genentech’s birth were dedicated to exploiting recombinant DNA for the mass production of natural products such as interferon and insulin for drugs. But the early germination of the modern biotechnology industry did not rest solely on recombinant DNA. By the 1970s a number of pioneering companies were developing Mab products, including Sera- Lab and two startups: Hybritech in San Diego and Centocor in Philadelphia. Entrepreneurs who risked entry into the field had no guarantee of success and were entering totally uncharted
territory. Such individuals faced major fi nancial, personal, professional, and regulatory challenges as well as a great deal of hostility, pessimism, and litigation.

Milstein with Köhler at the time of their receiving the Nobel Prize in 1984 together with Nils Jerne.

Mabs have had their strongest therapeutic impact in the field of cancer. The first Mab to reach the market for cancer was edrecolomab (Panorex), which was granted German regulatory approval in 1995 for the treatment of postoperative colorectal cancer. Developed by Centocor in partnership with the Wistar Institute, it was withdrawn in 2001 because of its poor effi cacy in comparison with other drugs. Since 1997, however, the U.S. Food and Drug Administration (FDA) has approved twelve Mab drugs for cancer treatment, including rituximab (Rituxan), approved in 1998 for the treatment of non- Hodgkin’s lymphoma. By 2012 there were over 160 candidates in clinical trials for cancer, with seventy of them in phase III trials, the stage before a drug is submitted for regulatory approval.

Mabs have enabled the identification and characterization of cancerous tumors previously difficult to detect and diff erentiate from other tumors, thereby providing a better understanding of cancer. They have also opened a path to more personalized medical treatment. Trastuzumab (Herceptin), for example, was specifically developed to target HER2/neu, a protein overexpressed by tumors found in 25 percent of newly diagnosed breast- cancer patients