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

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

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.

Beyond the genome

FORUM Epigenomics. Roadmap for regulation. Diseases mapped

My suggestion for today. Have a look at the papers in Nature on epigenome, and at the following figure:

The Roadmap Epigenomics Project has produced reference epigenomes that provide information on key functional elements controlling gene expression in 127 human tissues and cell types, and encompassing embryonic and adult tissues, from healthy individuals and those with disease. a, Many of the adult tissues investigated were broken down by cell type or region — blood into several types of immune cell, for instance, and the brain into regions including the hippocampus and dorsolateral prefrontal cortex. Tissue samples and cells were subjected to a range of epigenomic analyses, along with genome sequencing and genome-wide association studies (GWAS). b, Embryonic stem (ES) cells, which are taken from the embryo at the 'blastocyst' stage and can give rise to almost every cell type in the body, were used to analyse, for example, the differentiation of stem cells into different neuronal lineages. The ES-cell-derived cell lines underwent the same epigenomic analyses as the tissue samples.

The key article, here.Tissues and cell types profiled:

For decades, biomedical science has focused on ways of identifying the genes that contribute to a particular trait, or phenotype. Approaches such as genome-wide association studies (GWAS) identify locations in thhuman genome at which variations in DNA sequence are linked to specific phenotypes, but if the variant is located in a region of DNA that does not encode a protein, such studies rarely provide insights into the regulatory mechanisms underlying the association. In these cases, comprehensive epigenomic analyses can provide the missing link between genomic variation and cellular phenotype.

If this is so, why are governments reluctant to introduce a ban on genetic tests with spurious associations between genome and diseases?




PS. Manel Esteller in DM.

Medicine as a data science

THE PATIENT WILL SEE YOU NOW
The Future of Medicine Is in Your Hands

Maybe the title is the most confounding factor of the new great book written by Eric Topol.  Once you have finished reading it, you'll be convinced that he set the expectations to high, ordinary people should develop certain skills beyond their capabilities to apply such concept. I would say that a greater part of the medicine is in your hands, not medicine at all. The rationale behind the book is that medicine digitization allows patients to know more about their disease and how to "manage" it in certain cases. The most important thesis is that future medicine has to be considered a data science. And this is exactly the impact of the digitization of diagnostic and treatment: pervasive application of Bayes theorem in clinical practice, using big data and analytics.(Remember my archimedes posts, surprisingly Topol forgot it).
The book includes many topics that those that follow this blog it would sound familiar, i.e. ch. 4 about Angelina Jolie and BRCA genetic tests, a must read. And chapter 5 is a journey on the new omics of the medicine, a topic that I have also covered in the blog.
Nowadays, Eric Topol is the writer that is able to capture what's going on in medicine and its impact on society. That's why this book is a key reference of our time and I strongly recommend it.

PS. If you don't believe me, check Forbes, NYT, WP, WSJ.
PS. The book is also an invitation to change the current academic programmes for life sciences universities. Better now than later.

The hype over genetic tests

Implementation of a companion diagnostic in the clinical laboratory:The BRAF example in melanoma

Analytical validity is one of the three steps for any assessment of genetic tests, combined with clinical validity and clinical utility. Understanding how this process affects specific tests is not that easy.Fortunately you can find a detailed explanation of one of them:the BRAF genotype analysis in tumor tissue samples for identification of melanoma patients that can benefit treatment with BRAF inhibitors.
Once you begin to read the article you'll understand the complexity of being precise in a test. This is the reason why if specificity and sensibility is uncertain, different methodologies are needed (check Figure 1).
But how to do it?. How to set up external controls of quality?. All these issues are covered in this article, that explains what's going on in practical terms. I'm concerned if due to such complexity, all "genetic test talent" is not concentrated in one site of the organization-hospital, and many departments and services -oncology or cardiology- are developing their own genetic tests. Somebody should block this option before it is too late.

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

The uncertainty over genomics sequencing value in clinical decision making

Assessing Genomic Sequencing Information for Health Care Decision Making: Workshop Summary

"The value of genetic sequence information will depend on how it is used in the clinic", key statement that needs some elaboration. This is precisely what the IOM report does, you'll find in their pages the current situation about how genomics may impact in decision making. In chapter 5 you'll understand how an insurer decides about coverage of such tests according to 5 criteria:

1. The test or treatment must have final approval from appropriate governmental regulatory bodies, where required;
2. scientific evidence must permit conclusions about its effect on medical outcomes;
3. technology must improve net health outcomes;
4. the technology must provide as much health benefit as established alternatives; and
5. the improvement in health must be attainable outside investigational settings.

Unfortunately, if you start from the first one, you'll find a complete lack of references by governmental bodies on the approval of such tests. Therefore, I can't understand from the chapter how successful they are on such process.
While reading the book you'll increase your uncertainty about outcomes and value of genomic tests instead of reducing it. This was my impression. Let's wait for future good news, again.

PS. Summary of the report:
"Clinical use of DNA sequencing relies on identifying linkages between diseases and genetic variants or groups of variants. More than 140,000 germline mutations have been submitted to the Human Gene Mutation Database and almost 12,000 single nucleotide polymorphisms have currently been associated with various diseases, including Alzheimer’s and type 2 diabetes, but the majority of associations have not been rigorously confirmed and may play only a minor role in disease. Because of the lack of evidence available for assessing variants, evaluation bodies have made few recommendations for the use of genetic tests in health care."

The hole for genetic testing market entry

Technology Assessment on Genetic Testing or Molecular Pathology Testing of Cancers with Unknown Primary Site to Determine Origin
Update on Emerging Genetic Tests Currently Available for Clinical Use in Common Cancers

AHRQ has just published two reports of interest. The first is devoted  to assess the evidence on the analytical validity, clinical validity, and clinical utility of commercially available genetic tests for identifying the tissue of origin (TOO) of the cancer in patients with cancer of unknown primary (CUP) site. The second describes genetic tests that have applications in the common solid tumors (breast, lung, colorectal, pancreas, etc.) as well as tests that are used in hematologic cancers (leukemia, lymphoma) and are already available in clinical practice.While the first is an assessment, the second is informative.
There is still a third report to be released and meanwhile NRD explains its conclusions. Having selected 11 prognostic tests, only around half had evidence supporting their prognostic accuracy or clinical validity. Therefore the question is always the same: why these tests without evidence are on the market? Why have they been approved by the FDA?. There is a big regulatory hole to fill in.

False advertising

The concern over consumer protection is growing with new health technologies. This is not new, you may think. However the lawsuit by FTC against Genelink for misleading claims is the first case in a genetics testing company. Genelink said that they analyzed your DNA and afterwards send back nutritional supplements customized to your personal genome. The regimen, the company promised, was good for diabetes, heart disease, arthritis, insomnia and other ailments.On request by FTC, they were unable to confirm such promises.
Since you may find a similar test on the corner of the street, once again my question is: where is the regulator?

PS. Some months ago, was the FDA who asked 23and me to stop selling its genetics test kit.

PS. On DTC genetic tests, a good article.

Courts as market makers

Recent decision invalidating Myriad patents has had immediate results. The market of genetic tests on breast and ovarian cancer has new entrants. The price of the test has decreased 40% (!) in just four months after the resolution. More entrants are expected in the next future for more tests.
The question is still the same, is there any clear cost-effectiveness analysis available for such tests? Why homebrew tests (LDT) are beyond any regulation? Does any regulator care about all this issues?. The answer is: up to now, we can't see any efforts. Patents create artificial monopolies, courts may create markets when invalidate patents,  but patients are concerned about health improvement and value. In an asymetric information environment, the regulator can't take permanent holidays. Overdiagnosed population doesn't necessarily mean healthier population.

 Forbes Healthcare Summit 2013

Insurance Companies Enter A New World

Genome sequencing mess

Since the world is more complex than it used to be, it is our duty to prevent any further complication. However sometimes some individuals forget it. The anouncement of sequencing genome for 100.000 citizens in UK last December raised controversy and BMJ right now publishes a head to head on this issue.
This blog has remarked many times that if effectiveness of any benefit is undemonstrated, then value is uncertain and potential harm of its application exists.
The summary of the position against sequencing is the following one:

If we sequence individuals’ DNA and tell them that they are genetically predisposed to be slightly more at risk of common diseases, we may be doing them a great disservice, demotivating them from behaving sensibly. And the private sector will see a marketing opportunity for all sorts of clinically unnecessary and potentially damaging screening, with further negative and unintended consequences. Possessing the technical ability to do something new is not an immediate justification for going ahead with it, especially in such an ethically complex area. Good medical practice requires tests to answer a specific question with a reasonable expectation of results being interpretable and useful. Currently, whole genome sequencing in healthy individuals has nothing to offer clinically because most of the data generated are meaningless; the maxim first do no harm still holds.

However, a subtile strategy has emerged recently. The Wellcome Trust will  finance with 3.2 m € a pilot study in London to analyse 97 cancer predisposition genes starting in 2014. It's not by chance, it coincides with Angelina Jolie double mastectomy recent news, and the patent expiration in 2014 of BRCA genetic tests. Is this a philantropic affair? or market access strategy?. The answer is yours.

PS. Beware of nonprofit foundations working for profit. This is a succesful strategy for market access when regulatory constraints have been set up and transparency rules apply. In such cases free lunches exist suspiciously,  but in the long-run they always disappear, and the social cost is enormous.

PS. A call to challenge "Selling Sickness"

PS. Save the date Sept 10-12 to prevent overdiagnosis.

Economics of genomics

The Economics of Genomic Medicine - Workshop Summary

Just imagine for a while that you are concerned about economic implications of genomics and you invite a distinguished professor of genetic medicine - James Evans- to the introduction of a workshop at IOM. Instead of more is better, he sends a cautious message to the audience. And beyond the potential and valuable applications for those that are already ill,  he openly critizises the current trend towards the use of genetic tests for the healthy:

Assessing the risk of common diseases through whole genome analysis of a healthy person has received the most attention, but this attention “is somewhat misplaced,” Evans said. Currently, assessment of genetic risk alleles has “rather feeble predictive power” because the increased risks tend to be small. “From a clinical standpoint I don’t know what to do with patients who are at a 1.3 relative risk for colon cancer,” said Evans. “Am I going to hurt them by doing more intensive screening, or am I going to help them?”

"I know what almost everybody in this room is going to die of,” said Evans. “We are going to die of heart disease or cancer. . . . We are all at high risk for these maladies regardless of our [genomically determined] risk. And many at decreased risk for heart disease will still die of heart disease. So we are all going to benefit from interventions that lower heart disease. We don’t really need to target people. It doesn’t do anyone much good to tweak our estimation of an individual’s relative risk for common diseases which we are all at high absolute risk of developing anyway."

 “The old adage that an elephant for a nickel is only a bargain if you have a nickel and you need an elephant applies here. I am not sure most of us need that elephant. Even if free, perceived low cost is an illusion, because the misapplication of medical tests—and make no mistake, whole genome sequencing is a medical test—is very expensive,”

A clear message for geneto-enthusiasts and marketeers. Cost-effectiveness of genetic testing starts with assessing if they are effective. If not, any economic analysis is useless . This is obvious, but we do need to repeat it, just in case.

PS. Must read, Reinhardt's blog.

PS. A report to understand the financial markets' mess and why recovery is far by now.

Veure-les passar

El tema segueix sobre la taula. El debat sobre les proves genètiques i com regular-les preocupa a la FDA i encara que ja ha dit que cal aplicar els mateixos criteris que als subministraments mèdics (medical devices), hi ha molts dubtes sobre els detalls.

Els de Genomics Law Report expliquen el que ha passat a les compareixences recents. Si n'esteu interessats feu-hi una ullada.
Les preguntes clau:

Should the agency require proof of analytical validity, clinical validity and/or clinical utility prior to approving a particular test and, if so, what standards of proof should be required?
Should the agency regulate tests SNP-by-SNP, claim-by-claim or test-by-test, and what should be done to prepare for the inevitable arrival of tests based on whole-genome sequence data?
Should the agency oversee the labeling and advertising claims offered by companies in association with such tests?
Should the agency require companies to collect and submit data regarding the post-test benefits and harms and the actual (as compared to intended) uses of their tests?
Should the agency impose requirements on companies to prevent unauthorized testing, protect data privacy and limit companies’ ability to share genetic information without their customers’ consent?

While these questions, and countless more, will be critical to the development of sensible genetic testing regulation, one question clearly generates more and more emotional responses than any other:

Should regulators require some or all genetic tests to be routed through a clinician, or should tests be made available directly to consumers who desire them?

I mentrestant per aquí, les veiem passar...i ens costen una pasta...

PD. El gran Ferran Torrent representa una alenada d'aire fresc els diumenges, tant en directe a Rac1 com els comentaris a ARA. Cita Josep Renau: "Quan arribes a València i et menges una paella o una sípia t'oblides de la lluita de classes". I mentrestant els de FT ens recorden que "Valencia is burning"