Precision medicine: a deep breakthrough in life sciences paradigm

Bioscience - Lost in Translation? How precision medicine closes the innovation gap

It is not so easy to translate knowledge into practice, and this is the case of biosciences into clinical applications. However, recently this trend is accelerating and precision medicine is emerging. A new book gives us the highlights to understand precisely what's going on: Bioscience - Lost in Translation? How precision medicine closes the innovation gap.

Richard Barker (the author of 2030 - The future of medicine) says:

The classic definition of diseases has been in terms of the symptoms they cause and/ or where in the body they appear. This was the best that medicine could do when external observation of the patient was the only or primary means of diagnosing disease. The  powerful new tools of molecular biology are reinterpreting disease in terms of aberrant,
defective, or unbalanced molecular mechanisms at the cellular, organ, or organism level. Molecular level diagnosis becomes a real possibility. Such an approach brings effective therapy immediately closer. Molecular diagnostics can separate diseases with similar symptoms but different underlying causes— and often suggest a different starting point for intervention.

If this is so, what should we do?

The seven changes of mindset and of practice are:
1. Advance the molecular definition of disease and the application of systems biology. We need a more decisive move from a classic definition of diseases— in terms of the symptoms they cause and/ or where in the body they appear— to a definition in terms of aberrant, defective, or unbalanced molecular mechanisms at the cellular level. And we need to marry this with a recognition that singular target- based innovation rarely works: we need a systems biology approach.

2. Partner academia and industry in more collaborative, impact- oriented research. We need to extend the ‘open innovation’ approach in which academia and companies invest together and share IP. We need to define new pre- or non- competitive spaces, especially in work on disease mechanisms and disease models. And we need to provide for new types of links and incentives to break down the barriers between these two worlds. 

3. Move decisively to a more adaptive approach to development, trial and approval design. We need to build on successful experiments in more flexible trial design, development pathways, and regulatory appraisal to a globally accepted adaptive approach. This involves collaborative design of the evidence package needed to secure approval and reimbursement, and greater teamwork through the process. 

4. Create new reward and financing vehicles for leading edge innovation. We need to move from reward systems based purely on unit sales of products, irrespective of outcome, to rewarding innovators for positive outcomes, patient by patient. We also need to design financing mechanisms that bridge between cost- effectiveness and affordability. We must be able to accommodate high- cost precision therapies that offer cures and so generate long- term returns for the system.

5. Engineer tools and systems for faster and better innovation adoption and adherence. We need to move from reliance solely on promotion to doctors and passive patient participation to a disciplined approach to establishing new pathways of care. These will be based on modern behavioural science, clinical decision support, and other digital technologies.

6. Develop an infrastructure for real- world data- driven learning. We now have the opportunity to study in large populations how lifestyle and treatment choices lead
to outcomes, learning from every patient as if in a clinical trial. New analytical tools will empower this.

7. Bring patients into the mainstream of decision- making and engage them  hole heartedly throughout the process. It is time to move from a process and mindset in which patients are regarded as passive subjects for clinical trials and recipients of products and procedures. Their input and engagement needs to be sought along the whole innovation chain: on treatment benefits, acceptable risks, optimal clinical trial design, adherence support, and outcomes.

Highly recommended.

In search of the balance between government and market

THE LIMITS OF THE MARKET: The Pendulum between Government and Market

Thirty years ago I bought a book that was a key reference MARKETS OR GOVERNMENTS : CHOOSING BETWEEN IMPERFECT ALTERNATIVES. The focus was clear, the government should enter when there is a market failure and try to curb it. This was the message and has been the message for many years. Now we know that the approach was too simplistic. If you want to understand an updated approach to the same issue, check the new book by Paul de Grawe, THE LIMITS OF THE MARKET: The Pendulum between Government and Market. A well written and accessible book that helps to remake the arguments with the evidence of the past years. The chapters:

The Great Economic Pendulum
The Limits of Capitalism
External Limits of Capitalism
Internal Limits of Capitalism
The Utopia of Self-Regulation in the Market System
Who can Save the Market System from Destruction?
External Limits of Governments
Internal Limits of Governments
Who is in Charge? Market or Government?
Rise and Fall of Capitalism: Linear or Cyclical?
The Euro is a Threat to the Market System
The World of Piketty
Pendulum Swings between Markets and Governments

At the end of the book there are two issues that concern the author: inequality and the degradation of environment. The need for internation cooperation on taxation is critical for the first issue, and the functioning of democratic institutions for both. His final comment is a call for action:

The Myth of Sisyphus

Sisyphus was a Greek king who felt stronger and wiser than Zeus, and was punished for his hubris. He was sentenced to push a rock up a mountain every day, after which the rock would roll back down each evening. The following day Sisyphus had to start all over again, continuing for eternity. In his essay The Myth of Sisyphus Albert Camus gave an existentialist interpretation of this well-known Greek myth. Camus sees Sisyphus’s punishment as a metaphor for the absurdity of life. How should we deal with this absurdity, he wonders? One option is to commit suicide. Camus rejects this option. Instead he suggests that we should rebel against the absurdity of life by throwing ourselves into it, living intensely, and being creative. The revolutionary hero is the one who despite the absurdity and knowing that his rebellion will eventually achieve nothing, still sets the rock in motion and remains happy. ‘Il faut s’imaginer Sisyphe heureux’ (‘One must imagine Sisyphus happy’), Camus decided.
That is the position I would like to offer as a guiding principle for the end of this book. It will be extraordinarily difficult to prevent future catastrophes. It may even already be too late. (I am at least a little more optimistic than Albert Camus with his Sisyphus interpretation, which is very bleak indeed.) We have a small chance of preventing decline with the reforms I outlined above. But even if that does not work, we are left with the option of doing as Sisyphus did, of starting again each day. It is the only way of giving meaning to our existence. If we do not take action, our grand children will not forgive us for failing to try to save them. That in itself is sufficient motivation to persist.

Transforming the practice of care in the most inefficient and wasteful health system

The Smart-Medicine Solution to the Health-Care Crisis

Eric Topol provides clear insights for a wide range of life sciences issues, and some days ago he insisted once again on the need to reform US health system. Everybody is talking about financing and acces, and he focuses on organization. That's good to hear. I suggest a close look at the WSJ article. Although the scope is US, you'll find many comments that are absolutely useful for our health system (the public and specially the private one).

Our health-care system is uniquely inefficient and wasteful. The more than $3 trillion that we spend each year yields relatively poor health outcomes, compared with other developed countries that spend far less. Providing better health insurance and access can help with these problems, but real progress in containing costs and improving care will require transforming the practice of medicine itself—how we diagnose and treat patients and how patients interact with medical professionals.

And he backs a smart medicine practice:

Smart medicine offers a way out, enabling doctors to develop a precise, high-definition understanding of each person in their care. The key tools are cheaper sensors, simpler and more routine imaging, and regular use of now widely available genetic analysis. As for using all this new data, here too a revolution is under way. 

And the key integrative tool:

At the Scripps Research Institute, we are working with the support of a National Institutes of Health grant and several local partners to develop a comprehensive “health record of the future” for individual patients. It will combine all the usual medical data—from office visits, labs, scans—with data generated by personal sensors, including sleep, physical activity, weight, environment, blood pressure and other relevant medical metrics. All of it will be constantly and seamlessly updated and owned by the individual patient.

Good news (US only):

 Fortunately, serious ventures in smart medicine are well along. My colleagues and I at the Scripps Research Institute are leading the Participant Center of the NIH’s Precision Medicine Initiative, which is currently enrolling one million Americans. Volunteers in the program will be testing many of the new tools I have described here. The recently formed nonprofit Health Transformation Alliance, which includes more than 40 large companies providing health benefits to 6.5 million employees and family members, intends to address the high cost of health care by focusing on, among other things, the sophisticated use of personal data.

I have to say that his position is well grounded, it is not a fascination for technology. The true health reform starts with the practice of medicine. Completely agree.

Fotopres

Critical thinking in medicine

Testing Treatments
Els Tractaments, a prova

If you are interested in critical thinking about treatment claims, then now it is the time to read this book in english and catalan. You'll understand:

Why do we need fair tests of treatments?
What are fair tests of treatments?
What can be done to improve tests of treatments?
How can YOU help to improve tests of treatments?

And you'll find a review by Xavier Bonfill at Annals

Health as the capacity for action

The Patient as Agent of Health and Health Care.

Autonomy in Patient-Centered Care for Chronic Conditions

Currently the concept of health as the absence of disease is absolutely outdated. The goal of clinical care has moved towards health-related quality of life. I have to admit that this is more an aim than a reality, but many professionalos share this view. If this is so, then considering health as capacity for action becomes critical. Mark Sullivan explains this view in an outstanding book, specially on part 3 and 4.

The turn to HRQL arose from the recognition that observable characteristics of the body could not provide an adequate account of the overall burden of chronic disease on individual patients or on the population as a whole. But the HRQL concept merely tried to add the experience of the patient to a notion of health defined by observable damage to the body or objective disease. It is not adequate to talk about the subjective experience of objectively defined health states. Health is not an objective state because neither death nor disease are always bad for patients. Most patients now choose to limit the medical care they receive at the end of life because they do not see death as the worst possible outcome. Similarly, it is possible for older adults to live well despite multiple chronic diseases. HRQL has not provided a fundamentally new metric for health and has not succeeded in redirecting clinical trials or activity to a more patient centered set of goals.

Any adequate, comprehensive, and valid approach to health must focus on personal agency, or the capacity of the person to achieve his or her goals. This is the only way we will understand and achieve individual well- being. This personal agency is both a means to well- being and an intrinsically valuable component of it. We conceptualize health and well- being as capabilities rather than as objective or subjective states: “our capability to lead the kind of lives we have reason to value.” To explore and define a new sense of health as agency, we will need to understand the various ways in which health and action are related.

A deep view of bioethics and the concept of health, all together. Good read for this summer.

The value of lab testing in precision medicine

The Value of Diagnostic Testing in Personalized Medicine

Before Jevons, economists were unable to think on marginal terms. If price should be related to marginal utility, then cost pricing nowadays is outdated. However, when someone suggests value pricing, you must ask immediately about what is value for him, and maybe it is not the same than for me. A paper on lab testing and its value suggests the following:

The value of a diagnostic arises not because of its direct effect on a patient’s health but because of the information it provides on a patient’s likely response to a particular therapy. Personalized diagnostic testing reduces – though does not eliminate – the trial-and-error associated with empirical medicine, where physicians and their patients try an initial set of therapies and decide to continue or discontinue them on the basis of realized efficacy and side effects. In this manner, personalized diagnostic tests transform medical care from what economists call “experience goods,” whose quality can only be determined through consumption, to “search goods,” whose quality can be learned before  consumption

Personalized diagnostic testing offers several advantages over an empirical, trial-and-error approach to medicine. These benefits include the avoidance of side effects, potentially reduced financial costs of therapy (e.g., if a patient is identified as a likely nonresponder to an expensive therapy and the alternative is cheaper), potentially reduced opportunity costs of time – not just in terms of physician visits but also time lost on an ineffective or even harmful treatment, and improved or earlier access to effective care. Not only do patients receive value from personalized testing and treatment, but providers and health care systems benefit by avoiding ineffective, or wasteful, health care that accompanies less targeted, traditional treatment approaches. Specifically, a diagnostic test will be most valuable when the therapy being evaluated is expensive relative to alternatives, when side effects are frequent and severe (thereby making the empirical approach relatively less safe), and when delay from an alternate therapy can severely harm an individual’s health (e.g., metastatic cancer)

The concept is clear, its measurement is still uncertain.

Is there any justification for interventions that aren't cost-effective?

Ethics, priorities and cancer

This is one of the most challenging questions nowadays. Anthony Culyer sheds light n this difficult issue in a recent article applied for cancer care. These are his nine  arguments:

Argument 1: the whole health maximisation assumption underlying the approach is misconceived. health care is about more than just promoting health. Other objectives commonly include financial protection (e.g. from the out-of-pocket expenseof costly interventions), innovation, and all those listed earlier
Argument 2: innovation is stifled by the strict application acost-effectiveness threshold that is too low
Argument 3: the use of standard outcome measures, like theEQ-5D QALY or averted DALYs, underestimates the health benefits of cancer treatments
Argument 4: the assessment of benefit excludes the beneficial effects that treatment and its consequences have on those who care for cancer patients
Argument 5: the opportunity cost argument is weak. There are always efficiency savings that can be found in any systemwhich mean that the alleged sacrifice of health represented by the threshold is spurious. the actual sacrifice is much smaller
Argument 6: cancer is a scary disease and people who suffer from it deserve to have access to treatments that would fail aconventional cost-effectiveness test
Argument 7: for some cancer patients a costly and not very effective treatment may offer a “last chance” to someone in despair. such a situation might exist if no intervention of any kind existed for these patients or if the patient suffered from a rare form of cancer
Argument 8: cancer is a “severe” disease and should accordingly be given a higher priority than less severe diseases
Argument 9: many cancer patients have a short life expectancy even with treatment. a quasi-utilitarian argument might cite the law of diminishing marginal value: even small gains for such people are to be valued more highly than the same gains of equivalent quality of life for people with an already long expectation of life. alternatively, there is the more direct emotional appeal “Our moral response to the imminence of death demands that we rescue the doomed proof"

These arguments fall into two broad groups. Some are questionsof social value: how should we value health gains of particular kindsand should we value them differently according as they accrueto different people? Others are questions of fact: would informa-tion about the quantitative size of the effects in question lead us to conclude that cancer is indeed a special case? The burden of proof in both cases lies with those making the assertion that cancer is, indeed, special. That burden of proof is not impossible to bear.

Is cancer a special case? The question may apply to many diseases and will provide more difficulties than answers. In the end any analysis relies on distributive justice principles and according to different views you'l apply different prioritisation criteria.

PS. The article was published in a cancer journal. I was surprised by the new perspective by Tony Culyer.

PS. What do you think about a new cancer inmunotherapy service that may cost $750.000???

Le Corbusier Guitariste (1960)

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The farce of confidential drug prices (2)

Payers’ experiences with confidential pharmaceutical price discounts: A survey of public and statutory health systems inNorth America, Europe, and Australasia

Some months  ago I posted on confidential drug pricing. I said that this was the end of cost-effectiveness as we have known. Now a new article reflects the evidence of my words:

Confidential price discounts are now common among the ten health systems that participated in our study, though some had only recently begun to use these pricing arrangements on a routine basis. Several health systems had used a wide variety of discounting schemes in the past two years. The most frequent discount received by participating health systems was between 20% and 29% of official list prices; however, six participants reported their health system received one or more discount over the past two years that was valued at 60% or more of the list prices. On average, participants reported that confidential discounts were more common, complex, and significant for specialty pharmaceuticals than for primary care pharmaceuticals.

If confidential discounts are huge (>60%), as they are, any cost-effectiveness analysis is adhoc and its obsolescence undermines any result. This fact is the recognition that the pricing system is not working and we are under a procurement system. As I said some months ago:The time to finish such farce has come.

Genome editing: understanding CRISPR-CAS9

Excellent speech by Salvador Macip at Grifols Foundation conference on CRISPR (in catalan):

Compensating behaviour after nudging

Nudges that fail

Cass Sunstein shows in his las published article that nudging may fail, and explains the reasons and what to do. Great, I was waiting for that, because we need to disentangle the current approaches to nudging. the article tries to shed light, but in the end, uncertainties remain.

The general point is that any form of choice architecture, including the use of default rules, may have little or no net effect if people are able to find otherdomains in which to counteract it. The idea of compensating behavior can be seen as a subset of the general category of strong antecedent references, but it points to a more specifi c case, in which the apparent success of the nudge is an illusion in terms of what choice architects actually care about (Hirschman,1991).
What matters is welfare, not effectiveness (Sunstein,2016). A largely ineffective nudge may have positive welfare effects; an effective nudge might turn out to reduce welfare. A strong reason for nudges, as distinguished from more aggressive tools, is that they preserve freedom of choice and thus allow people to go their own way. In many contexts, that is indeed a virtue, and the ineffectiveness of nudges, for some or many, is nothing to lament. But when choosers are making clear errors, and when third-party effects are involved, the ineffectiveness of nudges provides a good reason to consider stronger measures on welfare grounds.

 Therefore with this text Sunstein is landing to the practical difficulties on nudging. Highly recommended.

PS. Congratulations to Adam Oliver, C. Sunstein and G. Akerloff for the new journal.

Pissarro à Eragny - La nature retrouvée

Au Musée de Luxembourg maintenant

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

Duan Michals exhibition in Barcelona

 

Are You What You Eat?

Are You What You Eat? Healthy Behaviour and Risk Preferences

I am not strictly a fan of economic experiments. They are useful, but usually researchers achieve conclusions from samples and settings that are far from what happens really in population and geographies. However, some days ago I was looking at an article that it seemed of interest. They try to:

estimate the degree of risk aversion for a sample of young healthy adults and we explore its links with a broad range of risky behaviours considered together. Second, as indicator of the overall quality of diet, we complement, for the first time, the BMI with the Healthy Eating Index (HEI), and we relate both to estimated risk preferences

Sounds good, because the use of Body Mass Index is absolutely outdated and its relationship with risk aversion is crucial. This is the summary:

Our results show that risk preferences significantly differ across young adults with different, not extreme, health conditions. In particular, they reinstate the importance of conducting analyses that look separately at the two sub-samples of female and male subjects . This allows disentangling the links and interactions between preferences and key health variables such as smoking, and also to fully account for the gender-specific effects of the BMI and of alternative indicators of healthy weight.

Second, in our sample young women do not show any significant robust associations between risk preferences and BMI. Third, for young men – but not women – the HEI index appears to be significantly and consistently associated with risk preferences: across all specifications, healthier nutritional habits, tend to be robustly associated with higher risk aversion. This, together with the lack of significance of BMI-based indexes, suggests that, for subjects with not extreme health conditions, there is a wide scope to use measures alternative (or complementary) to the BMI, as indicators of the overall quality of diet.

That's it. And his final recommendation:

 From a health policy perspective, our study suggests that in young adults who have not yet developed chronic or extreme health conditions, looking at a comprehensive nutritional indicator such as the HEI could provide more direct insights to the deeply rooted behavioural mechanisms that drive health behaviours than considering an indirect and increasingly questioned measure such as the BMI.

Since children's obesity is one of the main challenges for health improvement, someone should take into account this message.

PS. Eliciting risk and time preference, the 2008 key article.

 Nancy Vieira

Taxing unhealthy foods

The effect of prices on nutrition: Comparing the impact of product-and nutrient-specific taxes

Nowadays, many people is asking about evidence oon the impact of taxes for sugar sweetened beverages. The reason is that in Catalonia from May 1st. a new tax has been implemented.Two tax rates have been set in relation to sugar content: For drinks containing more than 8 grams of sugar per 100 ml: €0.12/litre. For drinks containing between 5 and 8 grams of sugar per 100 ml: €0.08/litre
A new article in the Journal of Health Economics sheds light on the issue:

Our main finding from the tax simulations is that nutrient-specific taxes have much larger effects on nutrition than do product-specific taxes, without causing a larger decline in consumer utility. The intuition for this result is that nutrient-based taxes have a much broader base, so it is more difficult to substitute away from any one good in response to such taxes. For example,a 20% tax on soda decreases total purchased calories by 4.84% and decreases sugar consumption by over 10%. However, a 20% sugar tax decreases total calories by over 18% and sugar by over 16%.The larger effect of a sugar tax on nutrition comes despite the fact that it has the same effect on indirect utility as a soda tax. Dueto their negative income elasticities and the patterns of own- and cross-price elasticities we find, taxes on snacks and packaged mealshave very small effects on nutrition. Fat and salt taxes, on the other hand, have much larger effects, decreasing calories by 19% and 11%, respectively. SSB taxes, which can be thought of as a hybrid price policy that targets a set of products based on their nutritional content, also are quite effective, reducing caloric intake by over 8%. However, these taxes are less-effective and only slightly less-distortive than a broad-based sugar tax.

If this is so, the next steps should be to review the initial impact and explore wether new approaches could be more succesful. Unfortunately the article doesn't explains the details of how to implement their result...

PS. On sugar

Ben l'oncle Soul

The challenges of medical practice variations

Medical Practice Variations

The title of this post is not original, it is really from a book published in 1990, 27 years ago! And Wennberg started such research on the 70's. What is new is the book "Medical Practice Variations" released last year. After all these years concerns have spread, methodological improvement is huge, and unfortunately evidence says that practice still shows wide range of variability. This is the main concern, what to do about it.
The description is excellent, 23 chapters and 527 pages reflect an effort of many years of several projects on the issue. A must read is the chapter 4, p. 53 by Enrique Bernal and his team: Medical Practice Variations in Elective Surgery. Variations may harm and produce waste, therefore understanding how to prevent low-value care is crucial. They say:

Two key steps in reducing low-value care, proposed by García-Armesto et al. (García-Armesto et al. 2013), are the following:
• Identifying those technologies ineffective in their usual indications or less effective than alternatives
– Dropping them from the benefits basket or making them subject to avoidable copayments
– Restricting indications to certain types of patients (choice guided by evidence of positive benefit/risk balance)
– Specifying and limiting the types of providers more suitable to offer each service (therefore substantiating indication becomes a requisite, discouraging irrelevant use)
– Capping the frequency or length of treatments
• Producing and making available guidance on a regular basis to reduce inappropriate use of procedures
– Highlighting and tackling unwarranted variations in elective surgery (naming and “shaming” to prompt query and change)
– Fostering best practices and improving coordination of care

As I said, a must read. Congratulations to the authors. Unfortunately the barrier is the price: $279. Notwithstanding that, health policy makers and managers should have it as a key reference for their decisions.

PS. If you want to know more about current projects, check the ECHO  website.