El valor de les proves diagnòstiques genètiques

Economic evaluation of next-generation sequencing techniques in diagnosis of genetic disorders: A systematic review

Supporting Biomarker-Driven Therapies in Oncology: A Genomic Testing Cost Calculator 

Aquest és un tema amb moltes singularitats i cal estar atents als detalls. Entendre el cost-efectivitat de les proves diagnòstiques obliga a precisar molt què es pretén i com la prova diagnòstica modifica la decisió clínica. És per això que s'hauria d'aplicar el cost per persona identificada correctament com a punt de referència clau. Ara bé això no és senzill de calcular.

Ara tots els ulls estan posats en seqüenciar l'exoma, i un article recent arriba a aquesta conclusió:

On the basis of the available evidence and present findings, exome sequencing as a cost-effective option could have the potential to be used as a genomic test to diagnose suspected genetic disorders. However, there is still no consensus among studies on performing the exome sequencing test as a first- or second-line diagnostic test. While NGS methods are usually implemented as the last diagnostic test by reason of their relatively high cost, a number of recent studies have indicated that when exome sequencing is  implemented as a first-line test, extra examinations avoided for diagnosed patients may amply compensate for the cost of the test.

Per tant deixa oberta la qüestió i no respon a la pregunta.  Jo crec que és qüestió de dies, seqüenciar l'exoma es convertirà en l'estandard.

PS. Més material.

Pandemethics (2)

 Pandemic Bioethics

Contents:
Chapter 1 Historical Epidemics
The Spanish Flu of 1918
Cholera
Plague
Smallpox
Yellow Fever
Malaria
Chapter 2 Modern Viral Pandemics
Polio
Asian Flu of 1957 and Hong Kong Flu of 1968
Ebola
Swine Flu of 1976
Human Immunodeficiency Virus (HIV)
SARS1
Swine Flu of 2009
Middle Eastern Respiratory Syndrome (MERS)
Zika
Other Viral Diseases Affecting Humans
Chapter 3 The Medical Nature of SARS2
Disputed Origins of SARS2
The Clinical Course of COVID-19
Transmission and Immunity
Chapter 4 Policies for Containment
Quarantine as a Preventive Allocation Strategy
Four Models of Fighting Pandemics
Successes and Failures around the World
Intermittent Lockdowns, Denial, and the American Confusion
Chapter 5 Who Should Live When Not All Can?
Ethical Theories as Guides
Historical Background: The God Committee and Social Worth
A Relevant Digression: “Sickest First” Allocation and UNOS
Enter Bioethicists
Saints and Sacrifice
Covid, Cognitively Challenged Patients, and Rights of Disabled Persons
Unexpected Allocation Issues
Chapter 6 Developing Vaccines
A Brief History of Vaccines
Kinds of Vaccines
Ethical Issues in Developing Vaccines
Speeding Up Development of Experimental Vaccines
Other Problems with Vaccine Trials
Politics and Vaccines for Covid
Chapter 7 Allocating Vaccines
Success with Quick Production of Vaccines
The CDC and the States
Ability to Pay and Access to Vaccines
Allocation Priorities
Vaccination Complexities
Mandatory Vaccinations
Global Vaccine Distribution
Possible Bad Scenarios
Chapter 8 Acts and Omissions, the Trolley Problem, and Prisoner’s Dilemmas
Acts vesus Omissions
The Trolley Problem
Prisoner’s Dilemmas and Vaccination Uptake
Chapter 9 Liberty and Privacy
Philosophical Positions on Liberty
Problems of Contact Tracing
Controlling Pandemics versus Protecting Privacy
Privacy of Genetic Information Collected during Testing in Pandemics
Chapter 10 Status Certificates
Defining Key Terms
What Is the Purpose of Status Certificates?
Benefits of Status Certificates
Problems with Status Certificates
Chapter 11 Structural Inequalities and Vulnerable Groups
Who Is Most Vulnerable in a Pandemic?
Differences in Efforts to Control Infection in Different Vulnerable Groups
Chapter 12 Leadership during Pandemics
Leadership and the Virtue of Trust
The WHO’s Leaders Made Mistakes
Donald Trump and American Leadership
Judgment of US Leaders during the Pandemic
Chapter 13 The Future
The Future of COVID-19
Lessons to Learn
More Pandemics Will Come
What Will Happen Next?

The value of direct-to-consumer tests

 Direct-to-Consumer Tests on the Market Today. Identifying Valuable Tests from Those with Limited Utility

For health care professionals, the analytical validity of DTC tests is a primary concern. Analytical validity of DTC genetic testing can be defined by analytical sensitivity and specificity whereby analytical sensitivity is defined as how often a test is positive when the genetic variant of interest is present in the tested sample, and the analytical specificity is defined as how often a test result is negative when the tested sample does not contain the genetic variant of interest.18 A recent study by Tandy-Connor and colleagues19 “indicated that 40% of variants in a variety of genes reported in DTC raw data were false positives” when compared with clinical confirmatory testing. This study highlights the need to scrutinize the analytical validity of DTC genetic testing and consider confirmatory testing in a clinical diagnostic genetics laboratory. 

Per the American Society of Human Genetics, “companies offering DTC genetic testing should disclose the sensitivity, specificity and predictive value of the test, and the populations for the information is known, in a readily understandable and accessible fashion.”

Unfortunately, nobody cares about it, and the regulator is still on vacation.

World Press Photo BCN

Bioethics for lab medicine

 Ethics for Laboratory Medicine

Key issues:

Table 1.Ethical Issues of particular importance in Laboratory medicine.

Informed consent 

Use of leftover specimens 

Biobanking 

Genetic testing 

Equity and access to laboratory testing 

Incidental findings and medically actionable results 

DTC testing 

Transfusion medicine and religious or ethical restrictions 

Disclosing medical error 

Emerging infectious diseases 

Test utilization 

The unique role of laboratorians, who care for patients but interact mainly with their samples rather than the person, creates distinct ethical dilemmas. In addition, laboratories function as critical parts of complex health systems, and the interaction of the laboratory with the greater healthcare system creates additional points of ethical friction (45). Clinical laboratory professionals are ethically bound to use our voices to advocate for excellence in patient care in the realms of respect for persons, beneficence, and justice, even in the face of technological, administrative, and, perhaps, clinical pressures to do otherwise.

Ethics represents moral principles based on cultural norms and values. Sometimes these moral values have been turned into federal or state laws or into local rules and regulations. However, laws and rules may be absent or difficult to apply to a given situation. When faced with ethical decisions, laboratorians should seek the input from other clinicians and laboratory colleagues. In addition, most hospitals have ethics boards comprising multidisciplinary teams of clinicians, lay people, and clergy to help guide decision-making.

 

Human genome 20 years later

Complicated legacies: The human genome at 20

On genome and precision medicine:

Debates about precision medicine (PM), which uses genetic information to target interventions, commonly focus on whether we can “afford” PM (17), but focusing only on affordability, not also value, risks rejecting technologies that might make health care more efficient. Affordability is a question of whether we can pay for an intervention given its impact on budgets, whereas value can be measured by the health outcomes achieved per dollar spent for an intervention. Ideally, a PM intervention both saves money and improves outcomes; however, most health care interventions produce better outcomes at higher cost, and PM is no exception. By better distinguishing affordability and value, and by considering how we can address both, we can further the agenda of achieving affordable and valuable PM.

The literature has generally not shown that PM is unaffordable or of low value; however, it has also not shown that PM is a panacea for reducing health care expenditures or always results in high-value care (17). Understanding PM affordability and value requires evidence on total costs and outcomes as well as potential cost offsets, but these data are difficult to capture because costs often occur up front while beneficial outcomes accrue over time (18). Also, PM could result in substantial downstream implications because of follow-up interventions, not only for patients but also for family members who may have inherited the same genetic condition. Emerging PM tests could be used for screening large populations and could include genome sequencing of all newborns, liquid biopsy testing to screen for cancers in routine primary care visits, and predictive testing for Alzheimer's disease in adults. These interventions may provide large benefits, but they are likely to require large up-front expenditures.

 

 

Clinical utility of genetic testing for breast cancer

 Breast Cancer Risk Genes — Association Analysis in More than 113,000 Women

Genetic testing for breast cancer susceptibility is widely used, but for many genes, evidence of an association with breast cancer is weak, underlying risk estimates are imprecise, and reliable subtype-specific risk estimates are lacking.

However,

 We found strong evidence of an association with breast cancer risk (Bayesian false-discovery probability, <0.05) for protein-truncating variants in 9 genes, with a P value of less than 0.0001 for 5 genes (ATM, BRCA1, BRCA2, CHEK2, and PALB2) and a P value of less than 0.05 for the other 4 genes (BARD1, RAD51C, RAD51D, and TP53).

  None of the other 25 genes in the panel had a Bayesian false-discovery probability of less than 0.10. Of note, 19 genes had an upper limit of the 95% confidence interval of the odds ratio of less than 2.0, with 2.0 representing a proposed threshold for “pathogenic, moderate risk alleles”9; we therefore conclude that these genes are not informative for the prediction of breast cancer risk. We confirmed that missense variants in BRCA1, BRCA2, and TP53 that would be classified as pathogenic according to clinical guidelines are indeed associated with clinically significant risks. We also found that rare missense variants in CHEK2 overall, as well as variants in specific domains in ATM, are associated with moderate risk.

The summary:

 Variants in 8 genes — BRCA1, BRCA2, PALB2, BARD1, RAD51C, RAD51D, ATM, and CHEK2 — had a significant association with breast cancer risk.

 

Precision medicine

 Precision Medicine for Investigators, Practitioners and Providers

Many topics under the same umbrella:

Table of Contents

Introduction

2. Role of genomics in precision medicine

3. High throughput omics in the precision medicine ecosystem

4. Infant gut microbiome

5. Paraprebiotics

6. Fecal transplantation in autoimmune disease

7. Drug pharmacomicrobiomics

8. CRISPR technology for genome editing

9. Engineering microbial living therapeutics

10. Organ on a chip

11. Multicellular in-vitro organ systems

12. The role of biobanks in biomarker development

13. Translational interest of immune profiling

14. Organoid pharmacotyping

15. Large datasets for genomic investigation

16. Modern applications of neurogenetics

17. Genomic profiling in cancer

18. Genomics in pediatrics

19. Genomics of gastric cancer

20.  Genomics of prostate cancer

21. MicroRNAs and inflammation markers in obesity

22. MiRNA sequencing for myocardial infarction screening

23. Cell free DNA in hepatocellular carcinoma

24. Non coding RNA in cancer

25. Germline variants and childhood cancer

26. Pharmacogenomics in cancer

27. Proteomic biomarkers in vireoretinal disease

28. Proteomics in respiratory diseases

29. Cardiovascular proteomics

30. Host genetics, microbiome, and inflammatory bowel disease

31. Sampling, Analyzing, and Integrating Microbiome ‘omics Data in a Translational Clinical Setting

32. Omics and microbiome in sepsis

33. Molecular and omics methods for invasive candidiasis

34. Lipid metabolism in colorectal cancer

35. Salivary volatolome in breast cancer

36. immunodiagnosis in leprosy

37. decision support systems in breast cancer

38. Electronic medical records and diabetes phenotyping

39. Clinical signature of suicide risk

40. Machine learning and cluster analysis in critical care

41. Artificial intelligence in gastroenterology

42. Algorithms for epileptic seizure prediction

43. Precision medicine in ophthalmology

44. Phenotyping COPD

45. Lifestyle medicine

46. Precision medicine for a healthier world

47. Aging and clustering of functional brain networks

48. Nutrigenetics

49. Genome editing in reproductive medicine

50. MRI guided prostate biopsy

51. Precision Nutrition

52. Theranostics in precision oncology

53. Precision medicine in daily practice

54. Imaging in precision medicine

55. Organoid for drug screening

56. Printing of personalized medication using binder jetting 3D printer

57. 3 D printing in orthopedic trauma

58. Consumer genetic testing tools in depression

59. The future of wearables

60. Tumor heterogeneity and drug development

61. Smartphone based clinical diagnosis

62. Smartphone biosensing for point of care use

63. Data security and patient protection

64. Blockchain solutions for healthcare

65. Ethical questions in gene therapy

66. Pitfalls of organ on a chip technologies

67. Regulatory issues of artificial intelligence in radiology

68. Academic industrial alliance

69. The future of precision medicine

70. Precision Medicine Glossary

71. Useful internet sites

The time to stop recreational testing has come

 Direct-to-Consumer Genetic Testing: Value and Risk

Piecing together information from a variety of sources, one reporter concluded that by early 2019, more than 26 million people worldwide had been tested by the four leading companies, 23andMe, Ancestry, Gene By Gene, and MyHeritage (1). That volume was fueled by aggressive marketing, including discounts in the lead-up to major holidays to promote gifting of test kits. As of May 2020, the  undiscounted price of the basic test offered by the leading companies was $59–$99.

This is an example of what should not had happened. Recreative genomics doesn't add value and increases uncertainty and anxiety. 

Although many consumers of DTCgenetic testing express an intention to modify their lifestyle to address risk factors, studies typically show no changes at follow-up (15, 30). In the PGen Study, 59% of participants said that test results would influence their management of their health (31). However, an analysis of the 762 participants who had complete cancer-related data found that those who received elevated risk estimates were not significantly more likely to change lifestyle or engage in cancer screening than those who received average or below-average risk estimates (44). It may be relevant that no participants tested positive for pathogenic variants in highly penetrant cancer susceptibility genes. As for population health, the Centers for Disease Control and Prevention identify three conditions—hereditary breast and ovarian cancer syndrome,Lynch syndrome, and familial hypercholesterolemia—that are poorly ascertained despite the potential for early detection and intervention to significantly reduce morbidity and mortality (45). The hope is that DTC genetic testing could improve the situation (15). However,DTC genetic testing as currently carried out is likely to fill gaps in haphazard fashion, given the characteristics of purchasers, the scope of available products, and integration issues.

One message. Right now and until we don't know the implications of recreational genetic testing, direct to consumers testing should stop.

Banksy

 

Next generation sequencing is knocking at the door (and the door is open)

Genetic testing: Opportunities to unlock value in precision medicine
Next-Generation Sequencing to Diagnose Suspected Genetic Disorders
Documento de consenso sobre la implementación de la secuenciación masiva de nueva generación en el diagnóstico genético de la predisposición hereditaria al cáncer

This week I've been reading three pieces on the same topic. First, a McKinsey insight on genetic testing, second a NEJM basic article that reviews the whole state of the issue, and third a consensus by three societies on how to implement next generation sequencing .
All of them are required reading for anyone interested in the topic. You'll notice that technology is knocking at the door and we do need to understand how to manage it. Otherwise it will enter anyway (without knocking) and then it will be more value extraction (by others) than value creation (for patients).
Unfortunately, what you'll not find in these articles is how to manage the introduction of the technology with organizational patterns, allocation and coordination of tasks and decisions. If you want some clues on this, read my previous post on Geisinger, they are applying what it seems to me the most appropriate perspective.

Sense Sal-Fins que surti el sol

The urgent need to define delivery models for genetic testing

Identification of Delivery Models for the Provision of Predictive Genetic testing in Europe: Protocol for a Multicentre Qualitative study and a systematic review of the literature

The increasing role of genomics in medical decision making requires a review on how services should be organised. Unless this effort is taken promptly, it will be much more difficult to adapt the messy organization to an efficient model for the delivery of services. This issues are explained in a recent article. The ten questions:

 The transfer of genomic technologies from research to clinical application is influenced not only by several factors inherent to research goals and delivery of healthcare but also by external and commercial interests that may cause the premature introduction of genetic tests in the public or private sector (i.e., introduction of a test despite insufficient evidence regarding its analytical validity, clinical validity, and utility). Furthermore, current genetic services are delivered without a standardized set of process and outcome measures, which are essential for the evaluation of healthcare services. It is important that only genetic/genomic applications with proven efficacy and effectiveness are delivered to populations, and particularly that technologies have favorable cost-effectiveness ratios

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

When science and regulation don't talk to each other

An Evidence Framework for Genetic Testing

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

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

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

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

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

New album by Txarango. Enjoy it!

The anxiety of inaccuracy

Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing

What happens if "one quarter of the clinical genetic results from commercially available multiplex cancer panels and reported at the PROMPT registry had conflicting interpretations" and if "36% of conflicting genetic tests results appeared to be clinically relevant, because they were either reported as pathogenic/likely pathogenic"? Does anybody care about it?.
I would suggest today you have a look at this article and your level of anxiety will increase suddenly.

Clinical data and genetic testing results were gathered from1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall,participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis.

Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management.

Therefore, 

Clinical interpretation of genetic testing for increased cancer susceptibility as assessed by multiplex panels hinges on accurate curation and interpretation of variants. Discrepant interpretation of some genetic variants appears to be common.

Take care. The regulator remains on vacation, a never ending vacation.

PS. On genetic testing 

 Vivian Mayer

Rethinking drug regulation and health risk mitigation

FDA in the Twenty-First Century. The Challenges of Regulating Drugs and New Technologies

A new book on FDA addresses the  "perennial and new problems and the improvements the agency can make to better serve the public good.". The book would deserve a detailed critique, however, let me skip directly to chapter 25: Device-ive Maneuvers FDA’s Risk Assessment of Bifurcated Direct-to-Consumer Genetic Testing.
In this blog I've written about the same topic. My position is clear: stop direct-to consumer testing. I have explained the rationale here. And what the book says, it is exactly the same:

Three steps are necessary to ensure the safety and effectiveness of DTC
genomic information. First, the underlying data must be analytically  valid—that is, the genomic data sequence must be accurate and precise. Second, the information must be clinically valid—the findings must be causally associated with clinical outcomes. And third, the risks of disclosing the genomic information must be minimized. FDA’s ability to effectively regulate genomic information hinges upon the approach taken to each of these challenges

Meanwhile, in Europe, nobody cares about it. It's a great shame.

 

 

La Lídia Pujol canta l'imne d'Occitània, "Se canta" (apelat tanben "Aqueres montanhes" en la Val d'Aran), dins lo programa de TV3 (Television de Catalonha) 

Learning occitan

Comunicat del 20 de genièr de 2016 del President de l’IEO sul tractament de las lengas regionalas per l’estat francés.
ASSASSINAR SEI LENGAS, ANSIN VÒU LA FRANÇA ?
L’Institut d’Estudis Occitans (IEO) denóncia aut e fòrt que l’Assemblada Nacionala ague fach rebuta a la proposicion de lèi de Paul Molac, relativa a l’Ensenhament immersiu dei lengas regionalas e a sa promocion dins l’espaci public e audiovisuau.
Per memòria, aquesta denegada vèn après : la promessa vana dau candidat Hollande sus la ratificacion de la Carta europenca dei Lengas Regionalas ò Minoritàrias (ambé lo debat mancat a l’Assemblada Nacionala), lo rapòrt Filippetti de julhet 2013 e sei 42 prepausicions passadas per malhas, tornat mai en octòbre de 2015 l’engatjament dau president de la Republica per la Carta, rebutat per la drecha senatoriala e que dire de l’ensenhament dei lengas regionalas assecat…
Convendretz que i a de qué se pausar la question.
Sorda que mai se pòt pas a la demanda populària, la França, es que vòu pas finalament assassinar sei lengas regionalas per de bòn ?
A la veritat, aquesta decision fa chifrar, notadament per son escart d’ambé la demanda sociala, e discredita lo foncionament democratic.
D’escondons, vesèm s’organizar l’eliminacion metodica de nòstrei lengas de l’espaci public republican.
Amb aqueste refús, la França demòra un còp de mai dins lo rodolet dei país reborsiers que donan ges d’estatut a sei lengas. Lo pluralisme linguïstic, pasmens, es una aisina de coësion indispensabla per la Nacion e un element de sa credibilitat internacionala.
Acceptar la postura dau Govèrn actuau de la França que mespresa de lengas que parlan sei ciutadans a milierats se pòt pas mai !
L’IEO demanda per aquò au Govèrn d’iniciativas nòvas que laissan oblidar lei còps que s’es mancat.
Coma lo digueriam encara en octòbre 2015 a Montpelhier, volèm una lèi !
Volèm una lèi que done un estatut vertadier ai lengas regionalas e garantisse sei locutors de tota exclusion e discriminacion.


Pèire Brechet
President de l’IEO

 

Lab tests and biomarkers regulation: a pending topic

La regulació de proves diagnòstiques i biomarcadors: una assignatura pendent

Pere Ibern

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

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

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

Introducció

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

La medicina estratificada

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

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

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

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

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

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

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

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

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

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

La medicina de precisió

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

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

REFERÈNCIES BIBLIOGRÀFIQUES

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

Organising genetic testing

Finally the government has decided to organise genetic counseling and testing. A recent instruction determines who does what. As you may remember I've said several times that government was on permanent holiday on this issue.
In this new instruction, at least two issues are forgotten: the tests that are covered, and the proliferation of sequencing instruments outside the lab. These are not minor issues.
Somebody should decide asap wether a test it is worth to be prescribed. Right now, there are no explicit constraints under the current instruction. And DNA sequencing instruments may be found in many departments under the consideration of research. If there is no clear split between research and care, I can imagine a close future with many messy labs within any hospital. Concentration of knowledge and specialisation provides wider guarantees for quality. Unless there is any mentorship program by clinical laboratories, things will go down the wrong path. Today I'm more worried than yesterday, unless these two issues are fixed.

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.

Opening the door to recreational genetics testing

On February 19th, the US Food and Drug Administration (FDA) authorized 23andMe to market a direct-to-consumer (DTC) carrier test for Bloom syndrome. Such test was classified as a medical device, and exempting it from premarket review. This may pave the way for DTC genetic testing in the US market.
The decision to open door for one test may represent the biggest move towards a recreational genetic testing market. You know that from this blog I have backed a ban on developing such markets and the need for an effective regulatory review different from the flawed medical device system.
The european regulator is still on holiday, I said that some months ago and it is still "out".

PS. Variations in health care in GCS Blog.

Do you really want to know about it?

Recreational genetics is entering into the consumer market. I have explained that governments should be active in restricting such practices because they are closely related with false advertising. Beyond that, governments should be aware also about the implications of creating anxiety in population. This documentary asks if patients should know about their genes, when there is no treatment.

La Noche Temática: '¿Realmente quieres saberlo?' -Avance

PS. Have a look at this one, about ethical dilemmas on genetic testing:

La Noche Temática: 'Descifrar nuestro código genético' -Avance

European health regulator on holiday

After Canada, the first european country that has allowed recreational genetic testing is UK. Some weeks ago the Ethics Research Committee approved the commercialisation of 23andme test that provides 100 genetic reports. Wired says:

The £125 spit test kit is not a diagnostic test, but instead identifies genes that are associated with inherited conditions including cystic fibrosis, Alzheimer's disease, Parkinson's disease and sickle cell anaemia. It's not just health information that can be discovered within the results of the test though -- there is also the opportunity for customers to learn more about their inherited traits and genetic ancestry.

Why has the UK approved it and the FDA has restricted the same test in the US?.  Some months ago I explained that european legislation was outdated. Now the genetic testing firm has profited from bad regulation to enter into european market with CE mark. Does anybody know where the regulator is spending their holiday?

PS. While being  so easy to regulate recreational genetic testing under current false advertising rules, why is only the US doing that?. You should know that closer than you think similar tests are available for you. Where is the catalan health regulator?

PS. Why is the tax regulator not on vacation?

Emile Claire Barlow - Jardin d'Hiver