Es mostren les entrades ordenades per data per a la consulta nice. Ordena per rellevància Mostra totes les entrades
Es mostren les entrades ordenades per data per a la consulta nice. Ordena per rellevància Mostra totes les entrades

13 de juny 2024

La innovació dinàmica als medicaments

 Achieving dynamic efficiency in pharmaceutical innovation: Identifying the optimal share of value and payments required

En diferents ocasions s'ha argumentat que l'avaluació del cost-efectivitat dels medicaments té en consideració tant sols una visió estàtica. La hipòtesi és que els fabricants posen un preu basat en un llindar de QALY acceptable d'acord amb el període de protecció de patent. En canvi s'oblida el valor post-patent, i que la quantitat i qualitat d'innovació que aporta en el temps no es considera. Jo no puc contrastar aquesta hipòtesi. El que si sé és que un article recent ha revisat la qüestió i diu:

The share of value that would maximise long-term population health depends on how the quantity and quality of innovation responds to payment. Using evidence of the response of innovation to payment, the optimal share of value of new pharmaceuticals to offer to manufacturers is roughly 20% (range: 6%–51%). Reanalysis of a sample of NICE technology appraisals suggests that, in most cases, the share of value offered to manufacturers and the price premium paid by the English NHS were too high. In the UK, application of optimal shareswould offer considerable benefits under both a public health objective and a broader view of social welfare. We illustrate how an optimal share of value can be delivered through a range of payment mechanisms including indirect price regulation via the use of different approval norms by an HTA body.

Per tant el valor transferit als fabricants és superior al desitjable al NHS. I la taula clau, allò que es paga i el que s'hauria de pagar segons els autors:

 

Els autors avisen de la simplificació d'alguns supòsits i de com els seus resultats difereixen d'altres aportacions. Tot plegat és una mostra més que és un camp fèrtil per a la recerca, i obert a nous horitzons i respostes.

26 d’octubre 2023

El llindar del cost per QALY se n'ha anat en orris

 Financing and Reimbursement of Approved Advanced Therapies in Several European Countries

El temps passa ràpid i aviat farà 50 anys que en Richard Zeckhauser (1976) va proposar els anys de vida ajustats per qualitat (QALYs) com a mesura per calcular el cost efectivitat incremental d'una intervenció sobre la salut i la vida. A data d'avui s'utilitza de forma sistemàtica a molts països per tal de conèixer el valor relatiu dels nous medicaments. Les mancances que té són moltes, i les he exposades en altres ocasions, però malgrat això és utilitzada per organismes reguladors.

Ara bé, quan la mesura del cost-efectivitat incremental la volem comparar amb el que una societat està disposada a pagar per un QALY, llavors tot s'entrebanca. I la mostra la teniu en aquest quadre que ensenya la situació. Si fa temps es parlava del llindar de 30.000€ per QALY, compareu-ho amb les xifres que surten i veureu que tot està fora de lloc. Poques teràpies avançades estan per sota, i la majoria per sobre i molt per sobre:


Tot plegat confirma, que la idea dels llindars de cost per QALY se n'han anat en orris. Si el cost per QALY no és un referent de la disponibilitat a pagar, aleshores quin és el referent 50 anys després de la seva creació? La mesura pot quedar relegada a un exercici comptable i res més. Per ara, anem donant pals de cec per aquí a prop. Mentrestant, el NICE té els seus criteris que ja està aplicant i que vaig explicar. Roman la incertesa, però hi ha criteris. 

A l'article hi trobareu també els preus notificats i alguns descomptes:



Són preus notificats, no són els preus pagats realment perquè a la negociació apareixen descomptes confidencials. I aquest és un altre problema dels QALYs publicats, si no sabem el cost final pel finançador, com podem dir quin és el cost per QALY?. Aquesta és una qüestió que queda a l'aire, almenys per ara.

A l'article hi trobareu molt més material d'interès per fer-nos una idea de la situació en aquest moment de les teràpies avançades, genètiques, cel·lulars i de teixits.

11 d’octubre 2023

Hem de parlar

We need to talk about values: a proposed framework for the articulation of normative reasoning in health technology assessment 

The normative grounds for NICE decision-making: a narrative cross-disciplinary review of empirical studies

Un dels moments més creatius del programa de TV "Persones Humanes" era quan sortia el Dr. Soler amb la secció "Hem de parlar". No era pas cap doctor, el seu germà si, però ell se'n deia i donava consells per a l'apassionant món de la parella. "Hem de parlar" és una frase que forma part del sistema 2 que diria Kahneman. En un món presidit per la immediatesa i les dreceres mentals per a la presa de decisions, aturar-se a reflexionar és molt recomanable.

Un primer article al que vull referir-me fa una revisió dels factors pels quals el NICE pren les decisions, i diu:

  1. Cost-efectivitat
  2. Incertesa
  3. Impacte pressupostari
  4. Necessitat clínica
  5. Innovació
  6. Raresa
  7. Edat
  8. Causa de la malaltia
  9. Impacte social
  10. Influència de les parts implicades
  11. Procés

i la conclusió és:

In conclusion, this review demonstrates that though NICE decision-making has historically been strongly influenced by concern for cost-effectiveness, this is by no means the only consideration. Many other factors have also been observed to play a substantive role in decision-making, interacting with each other in ways that appear complex and are yet to be fully understood.

Missatge d'interès per tots aquells que es focalitzen en excés en el cost-efectivitat normatiu sense modular com el regulador el duu a la pràctica. 

Llegeixo també un segon article que comença amb la frase, "Hem de parlar" i aquesta vegada és sobre els valors que incorpora l'avaluació de tecnologies sanitàries. Comença amb definicions, bona forma d'iniciar un debat:


i un esquema:


i conclou:

Decisions about which health care interventions to provide, and to whom, have substantial implications for the health and wellbeing of society and are fundamentally grounded in normative considerations about which reasonable people will disagree. These decisions must, therefore, be transparently reported and morally justified if they are to be seen as legitimate. At present, limitations in the language used to articulate normative reasoning are likely to undermine both perceived legitimacy and fairness.
The proposed framework provides a tool for more clearly articulating the rationale on which priority-setting decisions are based and allows decision-makers to be more explicit about how the available evidence has been evaluated, and the role that it has played in guiding them towards their conclusions. As such, it constitutes an attempt to strengthen the legitimacy of HTA as a tool for healthcare priority-setting and is offered for further debate and development by those in the academic and policy communities.

La legitimitat de l'avaluació de tecnologies com eina de priorització està en hores baixes. Ho vaig explicar no fa massa. Introduir elements com els que s'assenyalen pot ser d'interès, ara bé, convindria  abans desfer el camí de crear fons específics per malaltia que ha fet el NICE. Altrament es construiria sobre fonaments inconsistents. A Catalunya, tot plegat no afecta a res de res, l'avaluació de les tecnologies es troba a terra de ningú (no-man's land). I sabent-ho, encara n'hi ha que s'omplen la boca del mots sostenibilitat i accés i alhora no hi ha capacitat de definir instruments que ho farien possible.




01 de setembre 2023

Quan l'excepcionalitat promou la discrecionalitat a l'avaluació econòmica

 The Innovative Medicines Fund: a universal model for faster and fairer access to new promising medicines or a Trojan horse for low-value creep?

Ja fa anys que es va iniciar un mecanisme per capgirar l'avaluació de tecnologies al NICE. El 2010 es va constituir el Cancer Drug Fund amb 50m £ que al 2015 s'havia multiplicat gairebé per 7 i segueix així en 340m. Molts vam veure aquella operació com una forma de crear l'excepcionalitat dins l'avaluació econòmica, el cost-efectivitat podia quedar tocat i enfonsat a partir d'aquell moment. I si es començava pel càncer doncs ja no hi hauria argument per altres malalties. I si això passava al NICE, doncs també podia passar a altres països. 

Tal dit tal fet, en plena pandèmia, el 2021 es va crear el Innovative Medicines Fund pel mateix import que el de càncer 340m. Ara l'excepcionalitat total és de 680m  £. Els criteris d'assignació estan descrits sota del gràfic:


Un article recent ho comenta i al final diu:

In conclusion, the IMF, like the CDF, should be an exceptional route to patient access while providing the requisite evidence (mainly from RCTs) for reducing uncertainty about a drug’s clinical and cost effectiveness. Potential inclusion in the IMF should be limited to those cases where the major uncertainties can be addressed within the defined time frame. The notion of opportunity cost must not be ignored as IMF funding could always be used for other health services and technologies with strong evidence on effectiveness and value for money, which could improve overall population health.

Doncs bé, ja ho tenim. L'excepcionalitat creix i tinc la impressió que no té aturador, font de discrecionalitat o arbitrarietat?. Mals temps per a criteris objectius d'assignació social de recursos, mals temps per a l'avaluació econòmica. Recordeu sempre que la discrecionalitat és una font de poder polític i econòmic fantàstica (i font de corrupteles). Qui prova la discrecionalitat no la deixa, és addictiva.

PS. Tot això de moment no passa aquí aprop, els polítics consideren que no cal l'avaluació de tecnologies. 

PS. La meva opinió breu sobre avaluació econòmica a p.24 d'aquest document

30 de juny 2023

Cartilla de racionament (2)

 The Ethics of Health Care Rationing

El racionament és inevitable, vivim en un món de recursos finits. Però els nostres ulls i el nostre cervell fan com si no se n'adonessin. Passem de llarg del tema com a societat, mentre que com individus hi topem de sobte quan ens trobem a una llista d'espera o quan hem de pagar per una prestació.

En la reedició d'aquest llibre es tracten aquests temes:

  • What sort of distributive principles should we rely on when thinking about health care rationing?
  • What is the relation between ethics and cost-effectiveness in health care?
  • How should we think about controversies surrounding discrimination over disability and age?
  • How should we approach controversies surrounding rationing and the price of pharmaceutical drugs and medical therapies?Should patients be held responsible for their health?
  • Why does the debate on responsibility for health lead to issues about socioeconomic status and social inequality?
El concepte:

Rationing, in its broadest sense, is the controlled allocation of some scarce resource or good. It implies that limits are placed on the good’s availability. People who need or want the rationed good are restricted to getting it in a certain quantity or size or at a certain time. They are not free to use or consume it in the way they want.

I l'objectiu del llibre:

 Our aim in this book is to show you that health care rationing not only can be ethical, but also it must be. Our case is very simple. We shall argue that the rationing of health care resources is inevitable. It takes place in all health care systems – public or private, rich or poor. It is not only inevitable, it is actually ubiquitous as well. So you might consider it a necessary evil. But then it is crucial that it is done as ethically as possible to reduce its evil effect. Hence, you should care about the ethics of  rationing health care. It is not an oxymoron.

 Two relevant, basic moral ideas are the maximization of the benefits from the use of health care resources and the fairness of the distribution of those benefits.

En definitiva, explica clarament moltes coses que els decisors no volen sentir, o que fan veure que no ho senten i així passen de llarg del tema. La política sanitària propera fa temps que prefereix la discrecionalitat a la transparència del cost-efectivitat. No és cap casualitat que no hi hagi cap CATNICE, una experiència catalana semblant al NICE



 

11 d’abril 2020

How pandemics shaped our world

Germs, Genes, & Civilization. How Epidemics Shaped Who We Are Today

From Chapter 11:
In his futuristic work The Shape of Things to Come, published in 1933, H. G. Wells relies on a novel plague to eliminate half the population of Earth in 1955–1956 and usher in a new era. Although this epidemic was largely modeled on the Black Death, Wells had his “maculated fever” waft around the world on the wind instead of spread by fleas. His fictitious disease emerged from captive baboons in the London Zoological Gardens. The Shape of Things to Come was written as a prediction of the future in an age when most scientists foresaw only the eventual eradication of infectious disease, not its resurgence.
So what should we predict? First, let’s consider the global situation. The British Empire was the last great civilization. Improved hygiene, originating from the industrialized West, led to worldwide decreased infant mortality. That, in turn, created a population boom that undermined the profitability of the European colonial empires. Despite poor hygiene and rampant disease relative to the industrial nations, the birth rate still outstrips infant mortality in Third World countries. The ongoing population explosion is the single most important biological trend in today’s world.
Denser populations, coupled with poverty, are promoting the spread of disease. Although tuberculosis is in the lead right now, most of those infected do not fall ill. As the remaining sensitive humans are weeded out, the incidence of TB in the Third World will begin to decline naturally, just as it did in Europe a century ago.
In the advanced nations, AIDS will affect homosexuals and intravenous drug users but have marginal impact on the mainstream. Its major effect, especially in the United States, will be to increase the cost of health care in the inner cities. This will help enlarge the growing gap between rich and poor. In Africa and, to a lesser extent, other third world regions, AIDS will thin out the promiscuous and malnourished, and favor the spread of religious puritanism, particularly, Islamic sects.
Still more serious, in my opinion, are malaria and other insect-borne infections that are spreading in the tropics. Rising world temperatures promote the spread of insects that transmit many tropical or subtropical diseases. Human construction and irrigation projects are helping, as is the steady increase in insecticide resistance among the insect carriers. An ugly long-term threat is the possible adaptation of tropical viruses to be carried by insects that survive in colder climates

PS. Further reading

Fascinating classics written long ago that are still good reading:
Defoe, Daniel. Journal of the Plague Year. New York: New American Library, 1960. (Original edition 1723.)
Although a work of fiction, the author lived in times when the bubonic plague was still around.
Nightingale, Florence. Notes on Nursing: What It Is and What It Is Not. New York: Dover Publications, 1969. (Original edition 1859.)
For a nice little old lady, Florence Nightingale was amazingly blunt and opinionated. She made generals tremble in their shoes. She would have made Hillary Clinton wilt!
Most important modern works:
Ewald, Paul W. Evolution of Infectious Disease. Oxford: Oxford University Press, 1994.
Seminal work on the evolution of infectious disease from the modern genetic and evolutionary viewpoint. Rather academic.
Herlihy, David. The Black Death and the Transformation of the West. Cambridge, MA: Harvard University Press, 1997.
Expounds the idea that the Black Death was responsible for the emergence of Western democracy.
McNeill, W. H. Plagues and Peoples. Garden City, NY: Anchor Press, 1976.
The most important single source that summarizes and explains the idea that epidemics affected human history.
Zinsser, Hans. Rats, Lice & History. Boston: Little, Brown and Company, 1934. (Reprinted quite frequently.)
Classic on typhus fever and history from the viewpoint of a microbiologist.
Narrow in focus, yet fascinating:
Cantor, Norman F. In the Wake of the Plague. New York: Free Press, 2001.
How the Black Death remodeled European society.
Cockburn, Aidan, and Eve Cockburn. Mummies, Disease and Ancient Cultures. Cambridge, U.K.: Cambridge University Press, 1980.
Grmek, Mirko D. Diseases in the Ancient Greek World. Baltimore: Johns Hopkins University Press, 1989.
A selection of other interesting books:
Cartwright, Frederick F., and Michael D. Biddiss. Disease and History. New York: Dorset Press, 1972.
Crawford, Dorothy H. Deadly Companions. Oxford: Oxford University Press, 2007.
Diamond, Jared. Guns, Germs and Steel. New York: W. W. Norton, 1998.
Garrett, Laurie. The Coming Plague. New York: Penguin Books, 1995.
Oldstone, Michael B. A. Viruses, Plagues, and History. New York: Oxford University Press, 1998.
Preston, Richard. The Hot Zone. New York: Random House, 1994.
Wills, Christopher. Yellow Fever, Black Goddess: The Coevolution of People and Plagues. Reading, MA: Addison-Wesley, 1996. (First published in the United Kingdom by HarperCollins as Plagues: Their Origins, History and Future.)


PS. The exit of the lockdown

19 d’abril 2019

On the effectiveness of digital health technologies

EVIDENCE STANDARDS FRAMEWORK FOR DIGITAL HEALTH TECHNOLOGIES

Every other day we here about a new health app, and new digital advances in healthcare. Too often, any innovation is considered effective without any deep analysis. Now, NICE provides a guide for this specific issue.

The economic impact of a DHT can be assessed using an appropriate analysis of the economic information collected. The type of economic analysis done should be determined by the financial consequences of adopting and implementing the DHT from a payer or commissioner perspective. The appropriate level of economic analysis depends on the type of decision needed and likely financial commitment. To reflect the range of commissioning decisions associated with DHTs, we have proposed 3 levels of economic analysis (see table 8).
Many DHTs will start at a basic economic analysis level but, with additional information and data about the technology and its comparators, a more robust economic analysis can be undertaken. The higher levels of economic analysis needed depends on the financial commitment required including, for example, the level of upfront investment, the likelihood of opportunity costs and the certainty of the realisation of the benefits.


05 de setembre 2018

Khan el-Khalili based drug pricing

When is it too expensive? Cost-effectiveness thresholds and health care decision-making

In one week of difference, the same technology: CAR T-cells has had two different options for drug pricing. Last week, under NICE review the answer was no to Gilead, and yesterday was yes to Novartis. The first paradigm applied to Yescarta is well known: marginal effectiveness should be acceptable at an affordable cost (NICE). The second one applied to Kymriah is based on preferences and willingness to pay under confidential prices. It is also a well known system specially at bazaars like Khan el-Khalili in Cairo.
This is an example of how two systems are applied in practice and nobody cares about it. I'm concerned about transparency, and that's why I can't understand why with public money the expenditure is confidential. I would agree if somebody explain the budget impact that have been agreed, otherwise with public money Kahn el-Khalili system is not acceptable. After more than four decades, Torrance would ask himself if all this effort on cost-effectiveness analysis has had any sense to arrive at this point.
Anyway, the remaining question is: when is too expensive? This is precisely what this editorial asks. And the and the answer (?) is:
For deciding whether something is too expensive, thresholds are crucial. Depending on which perspective is taken, the word ‘threshold’ may either refer to the consumption value of health or the marginal cost-effectiveness of current spending. 
This is a standard health economics perspective that no health politician nowadays will buy. Right now they are not buying the idea, and I think that they prefer confidential prices. It allows to reflect power,  discretionality, or even worse arbitrariness. Khan el-Khalili system has won.

16 de juny 2018

Value creators and extractors

The Value of Everything: Making and Taking in the Global Economy

The rethorics of value is usually plagued with deliberate misunderstandings. Specially, those that quote themselves as value creators may appear on a close look as a value extractors. This is precisely what the book of Marianna Mazucatto does. It identifies the patterns to assess value creation and extraction and the private of public and private roles.Chapter 7 on Extracting Value through the Innovation Economy is specially helpful. You'll find there the patents as a value extraction process or the pharmaceutical pricing discussed in detail. Therefore, a must read.
In modern capitalism, value-extraction is rewarded more highly than value-creation: the productive process that drives a healthy economy and society. From companies driven solely to maximize shareholder value to astronomically high prices of medicines justified through big pharma's 'value pricing', we misidentify taking with making, and have lost sight of what value really means. Once a central plank of economic thought, this concept of value - what it is, why it matters to us - is simply no longer discussed.
 The logical outcome of a combination of monopoly and rigid demand is sky-high prices, and this is precisely what is happening with specialty drugs. It explains why pharmaceutical companies enjoy absurdly high profit margins: in addition to the normal profit rate, they earn huge monopoly rents.59 A value-based assessment of the kind NICE carries out can be helpful because it reduces demand for the monopolists’ drugs and prevents them from charging whatever price they choose. The downside, however, is that increased elasticity of demand for drugs comes at the cost of leaving some patients without the medicines they need, because pharmaceutical companies may not cut their prices enough to treat everyone who needs the drug if doing so would reduce profit margins by more than the companies want.




31 de maig 2017

Controversies on QALYs

The Limitations of QALY: A Literature Review

After 50 years, valuing health using QALYs is still a daunting task. Basically the debate over ethical considerations, methodological issues and theoretical assumptions, and context or disease specific considerations is still alive. And I would add that it will remain as an open issue. Those that would like a simple metric for a complex issue will fail forever. And this pitfalls are translated to decision making when QALYs are the reference for resource allocation.
I'm unsure about what will be the next step. A recent article explains current limitations, but unfortunately I can't foresee alternative options for the future:

Debate continues to exist on whether QALYs should serve as the central means of health economics analysis. This review examines the potential shortfalls of QALYs, spanning current ethical, methodological, and contextual domains in addition to examining their suitability for regenerative medicine and future technologies. In the UK, NICE currently stipulates a threshold of £20 000 - £30 000 per QALY  when evaluating new therapeutics and/or technologies for NHS adoption, and has used this tool to apply a rational and transparent process to technological adoption for over ten years. Calculating QALY or cost effectiveness thresholds is particularly complex and debate has previously been publicized on whether the value of a QALY should be dictated by first proposing the worth of a QALY and setting the healthcare budget at or below that value, or alternatively, proposing a healthcare budget and then allowing the cost of a QALY to declare itself following purchasing decisions. With the advent of cellular based therapeutics and their comparably high upfront costs, the QALY calculation methodology may need refinement to realise the financial advantages and opportunity costs such interventions may convey – particularly considering the degree of uncertainty associated with them.
Meanwhile we should focus on improving comparative effectiveness of current and new technologies, specially those that are related to precision medicine.



 

 
Dr. Heisenberg's Magic Mirror of Uncertainty, 1998
 

31 de desembre 2016

The Voltaire of health economics

MAYNARD MATTERS
Critical Thinking on Health Policy

For any health economist, Alan Maynard is a reference. We've been reading his contributions for decades and now we can read a book (free to download) that has two parts. The first shows different views of his role on health economics and policy,  while the second is a selected collection of articles and book chapters.
I would like today to highlight what Rudolf Klein says about what he calls "The Voltaire of Health Economics":
I am sceptical about some of the claims to special policy wisdom of economists operating in
the health field. Too many, I find, seem to have a naive faith in QALYs, reflecting methodological innocence and an unreflective utilitarianism. Too many, in my view, appear to think that evidence should guide policy action in situations where only policy action can produce the evidence. Too
often I find myself bemused by statistical wizardry, wondering whether the inevitable simplifications required by modelling don’t exclude crucial dimensions of a complex world
The reasons for my admiration stem from Alan’s specialcombination of energy, moral drive and irreverence.  
Alan is a moralist. For him a failure to act on – or, if need be, generate – the evidence for a policy intervention is an ethical failure. So identifying what interventions give the “biggest bang for the buck” is the moral obligation of all policy makers. He sees a reform of the NHS, or indeed of any health care system, “as an experiment on fellow citizens”, which has to be justified and undertaken responsibly, and not on some ideological whim.
I agree absolutely on Rudolf Klein views.
In chapter 13 you'll find a book chapter "Health Economics: Has it fulfilled its
potential?" that is abstracted by the editor's with this words:
Whilst Maynard argued strongly for the importance of generating and using cost-effectiveness data in decision making, he was concerned that this had encouraged an industry of health economists rolling out economic evaluations. The victory of the health economics perspective in how to ration health care resources led to health economics becoming the slave of the cost-effectiveness industry, feeding regulators such as NICE and also the pharmaceutical and device manufacturers seeking to get their products approved and funded. This distorted the role of health economics and only used a small part of the full repertoire of perspectives and techniques that economics could apply to health and healthcare problems. He argued here that health economists need to keep a strong link with economics as a discipline and apply themselves to a wider range of problems such as supply and demand, the workforce, incentives and behaviour change, pricing and equity.
 As the front page says:
Brilliant, irreverent and almost always right – essays by a sceptical health economist who changed the way we think about policy
A must read.

PS. The best books of 2016 by FT




09 de desembre 2015

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.
Article en pdf
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.

24 de febrer 2015

Thresholds' controversies

Guidance on priority setting in health care (GPS-Health): the inclusion of equity criteria not captured by cost-effectiveness analysis

The threshold for cost-effectiveness is under controversy again. This is not new. FT explains a new York University paper that has created great concern. Is it NICE cost-effectiveness way of implementation really "cost-effective"?. From their point of view, thresholds are higher than they should be to guarantee access.
Thresholds are only one side of the coin. The other one is the introduction of equity criteria in cost-effectiveness analysis. Three years ago, I explained this topic in a post commenting on Tony Culyer''s article. He says that there are two "dragons" in dealing with cost-effective analysis: equity and our ignorance about how to introduce it. I then quoted this statement:
‘Arguably the biggest threat to our public health care system is not our ability to pay for the increasing cost of care, but rather a loss of public confidence.’’
An older post on Eddy's work explains similar concerns over thresholds and equity. We have to convene that there is not only one method to do it. However, some well known academics have published an interesting proposal: criteria for access to be considered jointly with cost-effectiveness.
The GPS-Health incorporates criteria related to the disease an intervention targets (severity of disease, capacity to benefit, and past health loss); characteristics of social groups an intervention targets (socioeconomic status, area of living, gender; race, ethnicity, religion and sexual orientation); and non-health consequences of an intervention (financial protection, economic productivity, and care for others).
Basically, these criteria are well known. The difficulty of its measurement has yet to be overcome.

PS. My former post on the same topic and authors in York. 

31 de gener 2015

The challenge of setting fair priorities

Public views on principles for health care priority setting: Findings of a European cross-country study using Q methodology

The clash between equity and efficiency is featured nowadays with hepatitis C drugs. High prices mean that access requires some kind of prioritisation. An interesting article may help to understand it:
 Resources available to the health care sector are finite and typically insufficient to fulfil all the demands for health care in the population. Decisions must be made about which treatments to provide. Relatively little is known about the views of the general public regarding the principles that should guide such decisions
The tension between equity and efficiency in the health care sector is apparent in a range of routine decisions and practices. For instance, in the prioritisation of patients on a waiting list, the aim to maximise overall health benefits from treatment may be at conflict with that of obtaining an equitable distribution of health and health care.
 Now ask yourself about the following principles to allocate health resources:
(I) “Egalitarianism, entitlement and equality of access”;
II) “Severity and the magnitude of health gains”;
(III) “Fair innings, young people and maximising health benefits”; 
(IV) “The intrinsic value of life and healthy living”; 
(V) “Quality of life is more important than simply staying alive”.
 Are you able to set a ranking? Does a general ranking of priorities always apply to all cases?. Not so easy. This is exactly what they do in the article and the results are:
Given the plurality of views on the principles for health care priority setting, no single equity principle can be used to underpin health care priority setting. Hence, the process of decision making becomes more important, in which, arguably, these multiple perspectives in society should be somehow reflected.
Let's think about the somehow...

PS. Sofosbuvir vs. NICE . And the winner is?

31 d’octubre 2014

On NICE and QALYs

It is quite relevant what's going on with value based pricing by NICE. Recent documents are raising greater controversy and a blog post asks if this is the end of the proposal. Today I suggest you have a look at James Raftery contribution to understand the moment (at least in the UK). No politician is interested in such issues.

19 d’agost 2014

Statistical vs. identifiable lives

Do We Really Value Identified Lives More Highly Than Statistical Lives?

The recent Ebola evacuated case exemplifies the concept created by Shelling a long time ago, the difference of how a society allocates resources according to 2 different rules:
In 1968, in a paper about valuing ways to reduce the risk of death, Thomas Schelling1 distinguished between “identified lives” and “statistical lives.” Identified lives are the miners trapped in a mine or the child with a terminal disease—specific people who need help now. Statistical lives are those people, unidentifiable before the fact and often after as well, who will be saved by a new safety regulation, public health program, or environmental standard. Schelling observed that people seem to be willing to pay more to save an identified life: “Let a six-year-old girl with brown hair need thousands of dollars for an operation that will prolong her life until Christmas, and the post office will be swamped with nickels and dimes to save her. But let it be reported that without a sales tax the hospital facilities of Massachusetts will deteriorate and cause a barely perceptible increase in preventable deaths—not many will drop a tear or reach for their checkbooks.
Really such a case goes beyond Shelling insight because of uncertainty and unavailability of effective treatment. Bioethics field has argued over what they called "rule of rescue", a different perspective of the same issue. In this respect, NICE statement helps to understand both views:
When there are limited resources for healthcare, applying the ‘rule of rescue’ may mean that other people will not be able to have the care or treatment they need. NICE recognises that when it is making its decisions it should consider the needs of present and future patients of the NHS who are anonymous and who do not necessarily have people to argue their case on their behalf. NICE considers that the principles provided in this document are appropriate to resolve the tension between the needs of an individual patient and the needs of present and future users of the NHS. The Institute has not therefore adopted an additional ‘rule of rescue.
The article by Louise B. Rusell reflects precisely the theoretical and practical controversy and ends with this paragraph:
Adjustments and controversies aside, the evidence provided by VSL estimates suggests that people’s willingness to pay for statistical lives may be consistent with their willingness to pay for identified lives. The apparent existence of 2 different decision rules may have been no more than an artifact of the economic method for valuing statistical lives in use at the time the distinction was proposed. Now that economists’ methods more fully reflect “the interests, preferences and attitudes to risk of those who are likely to be affected by the decisions,” their estimates of the value of a statistical life support the idea that there just may be a single rule: Identified and unidentified lives may be equally valuable. This is good news for decision makers who use cost-benefit and cost-effectiveness analysis to inform decisions.
The theoretical suggestion sounds good, nowadays the political decision making reality goes in the opposite way, at least close.

PS. A must read post on GCS blog about the same topic.

PS. Ebolanomics, the economics of ebola at the New Yorker. Nothing new, prizes instead of patents to promote R&D, a good idea with difficult implementation.

PS. How much would you pay for a quality adjusted life year?

23 d’abril 2014

The drivers of HTA decisions

Decision making by NICE: examining the inuences of evidence, process and context

Two reductionists views can be avoided. There is one that puts all the eggs in one basket of QALYs, the opposite that considers that QALYs are flawed and the solution is far away. Beyond such extremes, there is the need to assess new techonogies, and this is precisely what NICE does. An interesting article revisits the current drivers used by NICE to take decisions. These are the conclusions:
The results suggest that the variability in decisions observed can be explained by a combination of clinical, economic, process and socio-economic factors. The analysis showed that the proportion of restrictions and non-recommendations issued by NICE are increasing over time relative to recommendations. The analysis also confirmed that the demonstration of clinical and economic value is central to NICE decisions.

New factors not previously reported to have an effect on NICE decision making were identified, including the effect of clinical superiority on NICE decision making, the effect of the ICER on the likelihood of both restriction and recommendation and that NICE decision making was sensitive to process variables as well as socioeconomic factors.
Interesting guide to convince those that already have a reductionist mind. The evidence, the process and the context has to be taken into account.

18 de març 2014

Futility labeling

Choosing Wisely — The Politics and Economics of Labeling Low-Value Services

As far as the evidence on effectiveness is uncertain in some cases, somebody has to put an alert on the population. Asymetric information is always moving towards some bias and favour those with better position. This is the moment for an independent body to disseminate information towards patients. In NEJM you'll find an article about Choosing wisely, an initiative already explained in this blog. An interesting objective, although the means could be controversial. Maybe professional associations are not in best position to assume such task. Kassirer (once again) reflected many years ago the relationships with industry and their conflicts of interest. My suggestion would be independent agencies, NICE style. They should inform population about what works, and they are already doing it.

05 de setembre 2013

A central dilemma

Reconsidering the Politics of Public Health

These are difficult times for public health regulators. JAMA highlights the issue:
A central dilemma in public health is reconciling the role of the individual with the role of the government in promoting health. On the one hand, governmental policy approaches—taxes, bans, and other regulations—are seen as emblematic of “nanny state” overreach. In this view, public health regulation is part of a slippery slope toward escalating government intrusion on individual liberty. On the other hand, regulatory policy is described as a fundamental instrument for a “savvy state” to combat the conditions underlying an inexorable epidemic of chronic diseases. Proponents of public health regulation cite the association of aggressive tobacco control, physical activity, and nutritional interventions with demonstrable increases in life expectancy
The article presents 5 ways towards a solution. The fifth says:
Physicians may bear particular responsibility in addressing the problem that psychologists call “hyperbolic discounting”— the human tendency to discount the value of future conditions bya factor that increases with the length of delay. Physicians bear witness to regrets about prior unhealthy choices in poignant moments— for example, the ex-smoker who wheezes in trying to keep up with grandchildren—and work to prevent other patients from experiencing avoidable fates.Perhaps physicians and other health professionals, as a result, have a special duty to weigh in on how society mitigates the social and environmental conditions that lead toward unhealthy choices
Wishful thinking again?.
Why should physicians bear such huge responsibility? "Nanny physicians"? What about citizens?. As you know, my focus is on shared decision making. Unfortunately the article doesn't mention it.

PS. What's goign on in Catalonia? Have a look at WSJ today. This is not a dilemma, it's a fact.

PS. Are you willing to pay 12.380€ for an additional survival of 36 days -progression free in breast cancer- ?. NICE considers that cost per QALY of Eribulin is 91.778 €. Are you willing to pay this cost? Forget the question,  there is no dilemma, the social insurance will pay it for you as from today. We are rich enough to afford it.

PS. If somebody wants to know how neuromarketing is being applied, have a look at the following documentary: "Don't think, just buy". Public health regulators can learn a lot from this experience to counter commercial efforts on junk foods and beverages.