For another day

The Actress, the Court, and What Needs to Be Done to Guarantee the Future of Clinical Genomics

The introduction of new technologies and benefits in health care is always a perfect chaotic process. It starts with the creation of great expectations that have to be fulfilled (and publicly funded!). In some sense it could be understood as a remake of the Nintendo story of undersupply and artificial scarcity creation. Some genome based biomarkers fits partly with this paradigm.
The case of Angeline Jolie -double mastectomy after BRCA testing positive- was broadcasted worldwide in the weeks before the ruling against gene patenting. Creating uncertainty and scarcity artificially is a heavier combination. And in this situations is when common good has to be protected, and government has the key role.
Two selected messages from this week in PLOS Biology:

If clinical genomics is about to move forward at a more rapid pace due to broader public awareness and a more favorable legal climate then there is still work to be done on the ethical, regulatory, and legal fronts.

Celebrities are now drawing public attention to the utility of genetic testing. With the Supreme Court decision opening the door to more and perhaps cheaper entry into the testing market, the requisite infrastructure for managing risk and the rules for handling risk information must be strengthened. Making testing more widely available will only be morally acceptable if there are rules of the road in place.

 Meanwhile, our regulator is just waiting for another day, then it may be too late.

Music video by Nikki Yanofsky performing For Another Day. 

(C) 2010 Decca Label Group

Improving the pharmaceutical regulation production function

Using Routinely Collected Data to Inform Pharmaceutical Policies

With the broadening of data available for officials to regulate markets, things could change. The issue is specially relevant for pharmaceuticals. Up to now if you want information about the market you have to use IMS data. Now governments that pay the drugs bill can use their own data to improve regulation. Better knowledge could represent better regulation if it is performed appropriately and on a timely basis. The OECD report tries to put all these elements together and highlight the opportunities ahead.

This report provides an overview of patient-level data on medicines routinely collected in health systems from administrative sources, e.g. pharmacy records, electronic health records and insurance claims. In total 26 OECD and EU member countries responded to a survey addressing the availability and accessibility of routinely collected data on medicines and their applicability to developing evidence. The report further explores the utility of evidence from clinical practice, looking at experiences and initiatives across the OECD and EU.

Governments will have to improve big data capabilities and add new talent.

Sorolla right now in London

Ara toca (prioritzar) (2)

La decisió d'ahir del NICE suposa tot un repte per a d'altres governs europeus. Va considerar que el fingolimod per a esclerosi múltiple no havia de ser finançat pel NHS. Destaco dos paràgrafs clau de la resolució:

In summary, the Committee believed that the manufacturer’s base case ICER for fingolimod of £55,600 per QALY gained compared with Avonex for population 1b was subject to considerable uncertainty and an underestimation of the most plausible ICER for the following reasons:

• Avonex is not an appropriate comparator for population 1b. Using more appropriate comparators such as best supportive care or Rebif-44 for population 1b increased the ICERs substantially. To establish the most plausible ICERs for population 2, a comparison with natalizumab would need to be considered.
• More plausible assumptions regarding the long term treatment effectiveness increased the ICERs.
• Inaccuracies in the administration costs employed in the model are likely to have led to an underestimation of the ICERs.
• Data chosen to model the natural history of disease progression were derived from a population that was unrepresentative of the current UK population with multiple sclerosis. This led to uncertainty in the model results.
• Utility data from the clinical trials should have been used in the model and supplemented by published sources only for estimates for higher EDSS scores not represented by the populations in the trials. This led to uncertainty in the model results.

The Committee concluded that an analysis that relied on a combined set of plausible assumptions (see section 4.17) would be certain to produce ICERs that substantially exceed the range it could consider to represent a cost-effective use of NHS resources. The most plausible ICERs for fingolimod for the treatment of relapsing–remitting multiple sclerosis in the base case population (population 1b) is likely to be above £94,000 per QALY gained compared with best supportive care and above £79,000 per QALY gained in the subgroup of population 1b in which people with rapidly evolving severe disease were excluded. Therefore fingolimod cannot be recommended as a cost-effective use of NHS resources.

Cal llegir el document sencer perquè esdevé més interessant comprendre l'avaluació de l'efectivitat abans que el cost-efectivitat. Les notícies que en sorgiran poden contenir biaixos interessats. Observo una preocupació per l'efectivitat que aporta i en canvi les notícies se centraran en el cost-efectivitat. Ara hi ha unes setmanes per avaluar aquesta decisió i després hi haurà la resolució definitiva.
El medicament ja està aprovat al mercat tant a UK com aquí i podria suposar un nou serial com va succeir amb Tysabri, si bé en aquell cas centrat en qüestions de seguretat.
L'esclerosi múltiple és una malaltia que demana noves teràpies però que hi ha dificultats fonamentals per l'abordatge. El NICE va mantenir un conflicte important amb els interferons ja fa uns anys. Ara amb aquesta decisió pot ser un pròleg de nova controvèrsia. Aquest conflicte es podria resoldre en primer lloc aportant dades sobre efectivitat o també canviant el preu, de fet el preu britànic és un terç inferior al dels USA, però no n'hi hauria prou. Podria ser que aquí la propera reunió de la comissió interministerial de preus ho aprovés sense cap anàlisi similar (preu aprox. tractament anual 22.000 euros). En definitiva, ara tocaria prioritzar sobre bases fonamentades i tinc la impressió que ho deixarem per un altre moment. Crec que per al regulador d'aquí tant li fa la decisió del NICE. Ara bé, i als ciutadans?.

Option value of healthcare technologies

 Broadening the Concept of Value: A Scoping Review on the Option Value of Medical Technologies

Key messages, 

Traditionally, cost-effectiveness analyses have been conducted from the payer perspective, although the question of whether they should be expanded to take a broader perspective continues to animate a lively debate. Lately, the attention has focused on wider components of benefits, including the so-called  option value. Our scoping review provides a comprehensive synthesis of conceptual and empirical aspects related to this topic recently introduced in the value assessment framework debate.

From a conceptual standpoint, the coexistence of 3 distinct definitions of option value in the literature emerging from our scoping review urges us to advocate for greater clarity of language in future research. We recommend using “insurance value” when referring to the utility of knowing that one may have access to a healthcare service should one need it in the future, as in definition A. Definition B mainly relates to decision making under uncertainty and specifically to the value of deferring uncertain unrecoverable decisions to a later time. In the evaluation of healthcare technologies and programs, this dimension of value originates from the possibility of delaying a reimbursement/adoption decision, if there is an expectation that better information on a technology’s (cost-) effectiveness will become  available in the future—for example, because a new clinical trial reports its results. Because this definition is rooted in financial options theory and its application to capital investment decisions, we recommend using the term “real option value,” consistently with the terminology used outside the healthcare sector 

According to the third definition, the claimed value does not originate from the uncertainty around a decision and the flexibility of deferring it, as in definition B, but rather it stems from the consideration that the value of a life-extending technology should also include the benefits of future treatments that otherwise would be precluded to patients if they did not benefit from improved survival. This definition of value pertains to the broader discussion on whether future costs and benefits not directly linked to the intervention being assessed should be accounted for when evaluating a technology.Therefore, we recommend that research related to this definition adopt the term “option value of survival.”

To date, no consensus has been reached yet

Les escaliers de la rue Chappe  à Montmartre.

A new missed opportunity

After all these years, a new proposal for regulating in vitro diagnostics and medical devices in EU is available. Current regulation was enacted in 1998, and this one could be applicable in 2022, 24 years after, pas mal for the busy politicians!.
And this is a proposal, there were previous unapproved proposals, and this one has to pass the Council and the Parliament. I will not enter into the details.
It was supposed to increase safety and efficacy, but the main problem remains with who has to enforce them. Notified bodies, a subcontracting regulatory firms network, with vested interests with industry can't claim independence. And specifically, the methods for evaluate the analytical validity, clinical validity and utility is uncertain. No regulator will confirm us that the cut-off values of diagnostic tests are set according to the best evidence and greatest benefit. In US, FDA is the responsible.
In summary, a new missed opportunity for european citizens. A greater risk and uncertain effectiveness in diagnostic tests and medical devices.

PS. The latest known example of the impact of wrong regulation is this one. Those affected can't read this blog, they are blind.

Josep Moscardó

Genetic testing: a knotty problem

Food and Drug Administration. Optimizing FDA's regulatory oversight of next generation sequencing diagnostic tests — preliminary discussion paper

Cutting the Gordian Helix — Regulating Genomic Testing in the Era of Precision Medicine

"Scientific progress alone won't guarantee that the public reaps the full benefits of precision medicine, an achievement that will also require advancing the nation's regulatory frameworks"

This strong statement reflects a wider concern on the implementation of precision medicine or stratified medicine. I have commented before on this issue, the NEJM article of this week clarifies the last attempt by FDA to shed some light and a specific approach to disentangle the current challenges. FDA has submitted a document for comments just to start a new era of regulation in health, a "collaborative framework" for creating reliable databases of genes and genetic variants underlying disease, and provide a "safe harbor" for the interpretation of genomic tests.
This is exactly the right direction. As long as, information is a public good, genetic testing -clinical validity and utility- should be provided only by the regulator.  Professionals and citizens need to trust in precision medicine and avoid snake-oil sellers.
Having said that, today I'm more concerned than yesterday on how our government is delaying to start such effort. Today is one more day lost.

Dufy at Thyssen Museum right now

PS. Somebody should think twice about the style of health policy debates in public TV.

To test or not to test (for coronavirus) (2)

Escaping epidemics through migration? Quarantine measures under incomplete

information about infection risk

Some days ago I was explaining the rationale for coronavirus testing regarding clinical decision making. However, as we all know, individual behavior is also capable to produce health and disease contagion. Therefore, in case of coronavirus, behavioral externalities are crucial and nowadays we have denominated them "social distancing". 

Having said that, there is an additional behavioral value from testing to take into account. If all individuals in a population have access to the test, maybe everybody is aware of social distancing than in a situation than only suspected cases receive the test. Behaviors may change, and quarantine strategies more successful. In such situation it is much more feasible to restrict mobility. Let's take for example what this article explains:

This paper studies the effect of public policies to restrict migration by individuals suspected of carrying disease, when those individuals do not know for certain whether they have the disease but may have more information than the authorities about their probability of being carriers. It has long been known that migration affects the spread of
disease, and this influence has for centuries been used to justify placing restrictions on the movement of individuals suspected of carrying infections.

 Epidemiological studies have addressed how individual behaviour, among other factors, affects the spread of infections. However, the study of how individual behaviour in turn
changes in response to the new incentives created by the occurrence of a disease is much less developed. The principal contribution of our paper is to bring the study of strategic behavior under uncertainty into the domain of epidemiology, and to analyze its impact, in interaction with public policies, on the overall impact of epidemic disease.

Migration as a form of preventive behaviour has received very little attention, although evidence has accumulated that migration behaviour and epidemics are intrinsically linked. Migration behaviour can respond very rapidly to changes in the health  environment, in particular when it suddenly deteriorates through epidemics.

In our model we show that:
• First, when the disease is concentrated in one place (the epicentre of an epidemic for instance), a decision to migrate away from the epicentre brings a potentially infected individual in contact with more uninfected individuals than she would have met had she
remained where she was. Thus the typical migrant imposes a net negative externality as a result of her decision to migrate, and the marginal migrant (for whom, by definition, private benefits of migrating just equal the private costs of doing so) has a negative
impact on social welfare. Laissez faire will therefore lead to excessive migration. This provides a rationale for the frequent (and frequently justified) public policy response to epidemics, which is to attempt to restrict migration away from the epicentre by those who may be infected.
• Secondly, and less obviously, not all policies that aim to restrict migration in fact do so. In particular, we distinguish two effects of quarantine policies. The first is that they raise migration costs, which lowers migration. For example, mandatory health certificates or test results may be required by health authorities to leave the epicentre of the disease.We call this a “type 1” effect of quarantine measures. The second effect is that they impose a utility cost on individuals of remaining in the city where quarantine measures are effective, since they face a chance of being subjected to awkward and possibly
dangerous restrictions on their movements. We call this a “type 2” effect of quarantine measures. Such measures impose a welfare cost on those who suffer them, which tends to increase migration by those who are not currently subject to quarantine but fear they may  become so if they remain where they are. Policies implemented without taking type 2 effects into account may therefore have results that are opposite from those intended.
• Thirdly, even policies that actually reduce migration may have an adverse impact on social welfare if they reduce migration “too much”, and specifically if they discourage those intra-marginal migrants whose private benefits from migration substantially
exceed their private costs of migration, by enough to outweigh the negative externality they impose on others. Overall disease prevalence may even increase if in the name of avoiding negative externalities the authorities discourage relatively low-risk individuals
from escaping the epicentre of the disease, thereby increasing the probability that they will catch the disease there from infected individuals.

When people have imperfect information about their own infection status, migration imposes net negative externalities by increasing the rate of exposure faced by the uninfected outside the epicentre of the epidemic. In and of itself, this our paper has highlighted the fact that although quarantine of individuals who have been identified as sick reduces (obviously) the propensity of these individuals to migrate and spread the disease, the threat of quarantine increases the propensity to migrate of other individuals who have not yet been fallen sick but who know themselves to be at risk.

Quarantine measures have all these effects. However, if information about contagion is confirmed, then behaviors may change, and mandatory health certificates can be issued. The case of the italian village of Vò confirms that population screening has been successful in stopping the outbreak. This could have been done at the beginning if diagnostics kits had been available. Right now it seems an unfeasible strategy. We know now that there is a behavioral value of test information, beyond the clinical value. And in the case of coronavirus, confirmatory tests provide only partial information. In case of non infection, incubation period is uncertain, and some days after can be confirmed. Therefore, quarantine measures have to be mandatory and strict for the whole population and for specific areas.