Nirvis (2)

 High drug prices are not justified by industry’s spending on research and development

Les dues retòriques per justificar els preus alts dels medicaments són: cal recuperar la inversió en recerca, i cal relacionar el preu amb el valor que aporten. La primera d'aquestes dues retòriques és la que s'explica a un article de BMJ. Són dades conegudes mostrades d'una altra manera. A la meva conferència a la Reial Acadèmia de Medicina del novembre passat ja ho vaig reflectir. La segona retòrica, la del valor, també apareix d'esquitllada a l'article, però sens dubte és el tema que es vol enfatitzar en aquest moment. 

El relat dels preus alts per recuperar inversió ja sap tothom que no se sosté per enlloc, i no cal donar-hi més voltes. I quan entrem en la retòrica del valor aquí hi podem trobar de tot, regles de rescat incloses. Per tant entrem a un camp minat, terres fangoses i sense cap concreció d'on anirem a parar.

Al final donen recomanacions al govern:

• Making national patent systems more stringent to avoid rewarding chemical novelty and inventiveness independent of added therapeutic value

• Clear communication by public health authorities to lay out health needs focused research and development priorities and the strategic use of public research funding to support them

• Smarter allocation of public research funds with retention of (partial) ownership that can be leveraged to pursue public health objectives, including affordable pricing

• Raising evidence standards for market authorisation by requiring companies to conduct comparative clinical trials designed to establish added therapeutic value whenever possible, and

• Reforming pricing and reimbursement systems to reward companies that develop drugs that deliver clinical benefit and discourage me-too and evergreening strategies

Llegiu-vos l'article i guardeu-lo. S'apropen els medicaments per l'hemofília i en sentirem a parlar dels seus preus i de l'impacte pressupostari. L'argument no serà la recerca, serà el valor que pressumptament aporten. Veig nirvis per totes bandes.

Banksy

Pharma returns

Measuring the return from pharmaceutical innovation 2018

Key findings for top 12 biopharma companies in the Deloitte study.

• R&D returns have declined to 1.9 per cent, down from 10.1 per cent in 2010 - the lowest level in nine years
• Returns have been impacted by the growing cost of bringing a drug to market which now stands at $2,168 million – almost double the $1,188 million recorded in 2010
• Forecast peak sales have declined from last year to $407 million – less than half the 2010 value of $816 million

The growing cost of new drugs includes buying companies for their research (outsourcing research) instead of "producing" R&D within the company. The report will not tell you this minor observation.
Last February I said :

In drug industry the probability of R&D failure is 90.4%. We all know that in the drug costs we are paying also for failures, but we easily forget the figure.

You'll not find any reference to this minor issue. Is there any profitable industry with such a failure rate?

Caro Emerald

Medicine trends

The future of medicine

A new supplement in Nature explains the main trends in Medicine. It is really helpful to have a quick look focused on those approaches that are the more promising for the next future. From the issue, I would pick one article: A CRISPR edit for heart disease, A one-off injection to reduce the risk of cardiovascular disease is now a prospect thanks to advances in gene editing.This is amazing, it changes current perspectives on the first cause of death worldwide (18 million people per year).

 In 2014, Musunuru and his team showed that more than half of Pcsk9 genes in the mouse liver could be silenced with a single injection of an adenovirus containing a CRISPR–Cas9 system directed against Pcsk9. This led to a roughly 90% decrease in the level of Pcsk9 in the blood and a 35–40% fall in blood LDL cholesterol⁴. Next, they used a mouse engineered to contain human liver cells, and tuned the CRISPR–Cas9 payload to target human PCSK9⁵. The team succeeded in showing that the human gene can also be switched off.

This is changing the focus of drug research, and a recent article explains the new approach.  Let's see if finally delivers what they say.

Fasten seat belts (3)

My former posts (1) and (2) alerted about the end of drug pricing as we have known and the begining of an opaque world where nobody knows how much money is involved in getting the value of a specific drug, except the manufacturer. The rationale for that are the confidential agreements between governments and drug firms. Up to now have been seven risk-sharing agreements, and beyond these, central government has set up additional five agreements. This latter agreements are really open-ended budgetary ceelings because it is difficult to estimate when the maximum amount is reached. This is precisely what it is explained by the official in charge of this issue in the journal.
Therefore we have changed the pricing system for an opaque open-ended budgetary ceeling system. It sounds incredible, but that's how it is. I can't believe that nobody worries about it.

PS. Genes and behaviour, on TE. I posted the initial research three years ago in this blog.

Pharma, big pharma (8)

 Drug Truths: Dispelling the Myths About Pharma R & D

This book answers the questions about the process and costs of pharmaceutical R & D in a compelling narrative focused on the discovery and development of important new medicines. It gives an insider's account of the pharmaceutical industry drug discovery process, the very real costs of misperceptions about the industry, the high stakes--both economic and scientific--of developing drugs, the triumphs that come when new compounds reach the market and save lives, and the despair that follows when new compounds fail. In the book, John LaMattina, former president of Pfizer Global Research and Development, weaves themes critical to a vital drug discovery environment in the context. This is a story that Dr. LaMattina is uniquely qualified to tell.

TABLE OF CONTENTS

PART I A MATTER OF THE HEART 1

CHAPTER 1 CHOLESTEROL DRUGS ARE UNNECESSARY 3

CHAPTER 2 INDUSTRY IS MORE INTERESTED IN "ME-TOO" DRUGS THAN IN INNOVATION 13

CHAPTER 3 IT TAKES INDUSTRY TOO LONG TO DISCOVER NEW DRUGS 23

PART II THE ROLE OF PHARMACEUTICAL R&D IN HEALTH CARE 39

CHAPTER 4 DRUGS ARE DISCOVERED BY ACADEMIA 41

CHAPTER 5 NEW MEDICINES ADD COSTS BUT LITTLE BENEFIT 50

CHAPTER 6 BIG PHARMA HAS FAILED AND SHOULD LEARN FROM BIOTECH SUCCESS 59

PART III THE PROFIT MOTIVE 69

CHAPTER 7 THE INDUSTRY INVENTS DISEASES 71

CHAPTER 8 NEW DRUGS ARE LESS SAFE THAN TRADITIONAL MEDICINES 79

CHAPTER 9 INDUSTRY SPENDS MORE ON ADVERTISING THAN ON R&D 91

CHAPTER 10 INDUSTRY DOES NOT CARE ABOUT DISEASES OF THE DEVELOPING WORLD 100

PART IV THE FUTURE 109

CHAPTER 11 BIG PHARMA'S DAY HAS PASSED 111

CHAPTER 12 FINAL REFLECTIONS 122

Stratified medicine in Europe

Stratified medicine in European Medicines Agency licensing: a systematic review of predictive biomarkers

The potential of predictive biomarkers for the development of stratified medicine has been highlighted for more than a decade. The current situation is very concrete. In Europe, EMA has accepted 49 biomarker-indication-drug combinations over 16 years, mostly used in cancer and as a predictive of drug efficacy, and in a minor scale of drug toxicity (4 cases).
These data confirm that currently the new wave of "personalised" or stratified medicine is really minor, although the investments and return expectations are huge.

Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas.

 Just released

Què hem de fer?

Using Market-Exclusivity Incentives to Promote Pharmaceutical Innovation

Sabem que la indústria farmacèutica investiga, però també que els medicaments que s'aproven cada vegada són menys, i generen més controvèrsia. Aquest article del NEJM ens diu el que s¡ha fet en termes d'incentius per a promoure la recerca i els dubtes raonables sobre el que s'ha assolit. Conclusió:

Although use of market-exclusivity incentives to promote pharmaceutical innovation has potential benefits, future legislative efforts aimed at encouraging investment in drug research and development should be more precisely designed to avoid waste and misuse, and they should be linked to demonstration of positive public health outcomes. Without these limitations, making exclusivity incentives available to pharmaceutical manufacturers may not be worth the potential risks to public health.

Extendre el termini de la patent pot ser contraproduent. Cal evitar el malbaratament. I això es relaciona amb el que deia fa uns dies, massa incentius provoquen que els errors els paguem molt cars.

Ps. Record de Juan Gris a Christie's 28m de $

Lliçons sobre política farmacèutica (3)

Regulation, Innovation and Competition in Pharmaceutical Markets

Si voleu un llibre introductori que descriu amb precisió el mercat farmacèutic aquesta és l'opció del moment. Els conceptes habituals necessaris per moure's bé en aquest entorn són explicats amb tots els detalls.

M'ha interessat especialment el tema de pagar per retardar l'entrada dels genèrics, els acords de pagament invers, perquè s'explica amb tota claredat una pràctica vergonyosa de la indústria que ja coneixia però que em faltaven peces.

Es tracta d'això:

‘reverse payment’ patent settlement agreements (also called pay-for-delay settlements), because they provide for the patentee to pay the alleged infringer, rather than the opposite (considering the standard expectation that a defendant would pay a plaintiff to settle), with the aim of delaying its market entry. In other words, in its typical scheme, the brand-name drug pharmaceutical company enters into an agreement with the generic competitor to settle the dispute and to limit its market entry in return for a transfer of value.1 Such transfer can take different forms, including either a direct monetary payment or another form of valuable agreement (eg an authorised licensed entry at a specific date, distribution agreements, favourable terms in a side deal in which the originator company grants a commercial benefit to the generic company), or both. 

Aquest és l'índex del llibre: 

Introduction 1

I. The Different Faces of Pharmaceutical Markets 1

PART I

1. Regulating Entry 15

I. The Main Features of Pharmaceutical Markets: The Supply Side and the Demand Side 15

II. The Product Life Cycle and the Costs of Innovation 20

III. The Access to the Market: Regulatory Approaches 23

A. The European Regulatory Framework 23

B. The US Regulatory Framework 27

IV. Concluding Remarks 33

2. Regulating Exclusivity 34

I. The Interplay between Regulatory Exclusivities and Intellectual Property Rights 34

II. Intellectual Property Rights in the Pharmaceutical Industry: An Overview on the Role of Patents 35

III. EU Supplementary Protection Certificate and US Patent Term Restoration 41

IV. Regulatory Exclusivity 48

V. Research and Bolar Exemptions 52

VI. Exhaustion Doctrine and Parallel Trade 59

VII. Concluding Remarks 63

3. Regulating Prices 64

I. Pharmaceutical Pricing and Reimbursement Systems in Europe 64

II. The US System 70

III. Concluding Remarks 76

viii Contents

PART II

4. Competition Law Enforcement in Pharmaceutical Markets: An Introduction 79

I. EU and US Antitrust Rules: An Essential Overview 79

II. Antitrust Enforcement in the Pharmaceutical Sector 87

III. Market Definition 95

IV. Concluding Remarks 100

5. Reverse Payment Patent Settlements 102

I. The Recurrence of Reverse Payment Patent Settlements in Pharmaceutical Markets 102

II. Reverse Payment Patent Settlements in the United States 105

A. Earlier Case Law and the Actavis Ruling 105

B. Critical Issues after Actavis 109

C. Further Developments 113

III. EU Case Law on Reverse Payment Patent Settlements 119

A. Lundbeck 120

B. Generics 123

IV. Comparative Analysis 127

A. Legal Frameworks 127

B. The Antitrust Assessment 129

V. Concluding Remarks 134

6. Product Hopping 136

I. Pharmaceutical Product Reformulations 136

II. Product Hopping before US Courts 140

III. The EU Experience 146

IV. The Antitrust Assessment of Product Reformulation 151

V. Concluding Remarks 155

7. Excessive Drug Pricing 157

I. The Resurgence of Excessive Pricing Cases in the Pharmaceutical Sector 157

II. Excessive Pricing under EU Competition Law 161

A. Aspen 165

III. The US Approach 169

IV. The Role of Antitrust Enforcement on Excessive Drug Prices 176

V. Concluding Remarks 178

PART III

8. Further Interactions: Pharmaceutical Markets, Intellectual Property and Human Rights 183

I. The Right to Health and Access to Medicines and the Relationship with Intellectual Property Rights: An Overview 183

II. Compulsory Licensing 191

III. Concluding Remarks 196

9. Public Health and Public Interest in Competition Law 198

I. Public Health and Competition Law 198

II. Competition Law and Non-competition Interests 203

III. Concluding Remarks 208

Conclusion 209

Bibliography 213

Index 233

MABS in history of medicine

The Lock and Key of Medicine Monoclonal Antibodies and the Transformation of Healthcare

While reading FT this summer I came across an article quoting a unique book on history of monoclonal antibodies (MABS). Right now there are more than 30 drugs in the market based on hybridoma technology that was created in 1975.
The birth of MABS is explained with full details, how the creators finally didn't patented it and why, the difficulties for research in an unconnected world, etc... An exciting story that is worth reading. Right now, it would be completely different, commercialization of research and medicine has raised considerably.

That a British company spearheaded the first marketing of Mabs, a technology devised in a British laboratory by an émigré Argentinian scientist with his German colleague, highlights the international nature of biotechnology commercialization. Sera- Lab’s venture to sell Mabs took place in the midst of the excitement generated by the founding of Genentech in 1976. The emergence of Genentech, which had been set up
to market recombinant DNA products, galvanized numerous alliances among academics, entrepreneurs, and venture capitalists to launch new companies to commercialize biotechnology. Most of the early enterprises set up in the wake of Genentech’s birth were dedicated to exploiting recombinant DNA for the mass production of natural products such as interferon and insulin for drugs. But the early germination of the modern biotechnology industry did not rest solely on recombinant DNA. By the 1970s a number of pioneering companies were developing Mab products, including Sera- Lab and two startups: Hybritech in San Diego and Centocor in Philadelphia. Entrepreneurs who risked entry into the field had no guarantee of success and were entering totally uncharted
territory. Such individuals faced major fi nancial, personal, professional, and regulatory challenges as well as a great deal of hostility, pessimism, and litigation.

Milstein with Köhler at the time of their receiving the Nobel Prize in 1984 together with Nils Jerne.

Mabs have had their strongest therapeutic impact in the field of cancer. The first Mab to reach the market for cancer was edrecolomab (Panorex), which was granted German regulatory approval in 1995 for the treatment of postoperative colorectal cancer. Developed by Centocor in partnership with the Wistar Institute, it was withdrawn in 2001 because of its poor effi cacy in comparison with other drugs. Since 1997, however, the U.S. Food and Drug Administration (FDA) has approved twelve Mab drugs for cancer treatment, including rituximab (Rituxan), approved in 1998 for the treatment of non- Hodgkin’s lymphoma. By 2012 there were over 160 candidates in clinical trials for cancer, with seventy of them in phase III trials, the stage before a drug is submitted for regulatory approval.

Mabs have enabled the identification and characterization of cancerous tumors previously difficult to detect and diff erentiate from other tumors, thereby providing a better understanding of cancer. They have also opened a path to more personalized medical treatment. Trastuzumab (Herceptin), for example, was specifically developed to target HER2/neu, a protein overexpressed by tumors found in 25 percent of newly diagnosed breast- cancer patients

Quan podem considerar que una malaltia és rara?

Defining rare conditions in the era of personalized medicine

Reforming EU and national orphan drug regulations to improve outcomes for patients with rare diseases

La OMS va considerar malaltia con aquella que té patró específic de signes clínics i símptomes que afecta 1 de cada 2.000 persones o menys. La Unió Europea diu el mateix, quan afecta a menys de 5 persones per 10.000, i ultra-rares 1 de 50.000. Amb el desenvolupament de la medicina de precisió sorgeixen noves qüestions que segons aquest article obligarien a reflexionar sobre la definició existent, tenint en compte que hi ha tres àrees a considerar:

• Subsetting of common conditions to rarer entities; for example, a common cancer subdivided by a specific biomarker

• Subsetting of rare conditions; for example, based on different specific variants in a gene that cause the condition

• Shared molecular entity conditions; for example, a ‘new condition’ comprising different diseases that have a shared (often drug-targetable) common feature.

Per tant, s'explica com els biomarcadors, la seqüenciació genètica i la teràpia molecular similar podrien ser els instruments per a definir malalties rares sota un marc nou. I conclouen:

Small-population research is increasingly recognized as a key part of the activities of pharmaceutical, medical technology and academic sectors, despite the challenges. If we are to maximize the benefits of twenty-first-century science, a common view of rare that incorporates the fast-evolving diagnostic landscape is needed. Reaching a consensus will strengthen the foundations of small-population research that can be applied to help develop approaches to address the high unmet medical need.

Tinc la impressió que els incentius a les malalties rares són necessaris, però també són contradictoris quan no assoleixen el que pretenen. Aquest altre article ho explica amb tot detall. 

Juana Francés, al MNAC

PS. Resum de la informació del dia. Queda clar, no es pot dir.

How to stop ineffective and harmful medical practices

Ending Medical Reversal: Improving Outcomes, Saving Lives

What are medical reversals? We expect that medicine will progress in a generally orderly fashion, with good medical practices being replaced by better ones. We used to use cholestyramine—a horribly tolerated drug that had no effect on patients’ life expectancy—to lower cholesterol after heart attacks. Now we use atorvastatin, a well-tolerated drug backed by robust evidence that it saves lives. This is how medical practice should evolve. Reversal, however, is different. Reversal occurs when a currently accepted therapy is overturned, found to be no better than the therapy it replaced. This often occurs when a practice—a diagnostic tool, a medicine, a procedure, or a surgical technique—is adopted without a robust evidence base.

 Instead of the ideal, which is replacement of good medical practices by better ones, medical reversal occurs when a currently accepted therapy is overturned—found to be no better than the therapy it replaced. Now, you might argue that this is how science is supposed to proceed. In high school, we learned that the scientific method involves proposing a hypothesis and testing to see whether it is right. This is true. But what has happened in medicine is that the hypothesized treatment is often instituted in millions of people, and billions of dollars are spent, before adequate research is done. Not surprisingly, sometimes the research demonstrates that the hypothesis was incorrect and that the treatment, which is already being used, is ineffective or harmful.

So what?

Our medical system is too tolerant of unproven practices. Doctors are too comfortable recommending a practice without real knowledge of whether it is helping or hurting patients. People are too willing to accept practices that seem like they should help. When a medical reversal does occur, most physicians consider it an exception to the rule. 

We need a culture change in medicine. We need to recommit to evidence-based medicine and realize that it is the only rational way to provide care. In this book we have provided a few suggestions for ways we can improve. We do not advocate that these recommendations be immediately implemented but that they be carefully considered, alongside recommendations proposed by other thoughtful analysts, and tested in prospective trials. As we move forward, we must recognize that drastic and dramatic change can often be harmful. We acknowledge that there will be areas of medicine in which, for now, we must tolerate the status quo. As we go through the house of medicine and clean up each room, we have to prioritize.  

Well, let's say that the book focuses on the shadows of medicine, but this is only one part. Generalisations are inacurate. Anyway, good to review it. And medical education is not enough to solve the issue, incentives and culture play a crucial role.

Regulatory capture (once again)

Hidden conflicts?

Nowadays, news on pharma industry capturing the regulator are not new. When everybody thought that some laws would provide a new ethical framework to avoid such capture, the result is exactly the opposite. It has improved and increased its sophistication. Have a look at Science and you'll understand what I'm saying.

An analysis of pharma payments to 107 physicians who advised FDA on 28 drugs approved from 2008 to 2014 found that a majority later got money for travel or consulting, or received research subsidies, from the makers of the drugs on which they voted or from competing firms.

 Of the more than $26 million in personal payments or research support from industry to the 17 top-earning advisers—who received more than $300,000 each—94% came from the makers of drugs those advisers previously reviewed or from competitors

 Through web searches and online services such as LinkedIn, however, Science has discovered that 11 of 16 FDA medical examiners who worked on 28 drug approvals and then left the agency for new jobs are now employed by or consult for the companies they recently regulated.

Definitely, the regulatory system is broken.

Atin Aya exhibition in Palafrugell

Against patents

The case against patents

Some months ago, a WP blog hightlighted a paper by Boldrin and Levine with a straightforward title. Now you can read it at the Journal of Economic Perspectives. The summary is in the first paragraph:

The case against patents can be summarized briefly: there is no empirical evidence that they serve to increase innovation and productivity, unless productivity is identified with the number of patents awarded—which, as evidence shows, has no correlation with measured productivity. This disconnect is at the root of what is called the “patent puzzle”: in spite of the enormous increase in the number of patents and in the strength of their legal protection, the US economy has seen neither a dramatic acceleration in the rate of technological progress nor a major increase in the levels of research and development expenditure.

A risky statement unless there is a clear support from research. However, once you continue reading you'll have arguments to be convinced about it. The impact on pharmaceutical industry is analysed in detail:

There are four things that should be born in mind in thinking about the role of patents in the pharmaceutical industry. First, patents are just one piece of a set of complicated regulations that include requirements for clinical testing and disclosure, along with grants of market exclusivity that function alongside patents. Second, it is widely believed that in the absence of legal protections, generics would hit the market side by side with the originals. This  assumption is presumably based on the observation that when patents expire, generics enter immediately. However, this overlooks the fact that the generic manufacturers have had more  than a decade to reverse-engineer the product, study the market, and set up production lines. Lanjouw’s (1998) study of India prior to the recent introduction of pharmaceutical patents there indicates that it takes closer to four years to bring a product to market after the original is introduced—in other words, the fifi rst-mover advantage in  pharmaceuticals is larger than is ordinarily imagined. Third, much development of pharmaceutical products is done outside the private sector; in Boldrin and Levine (2008b), we provide some details. Finally, the current system is not working well: as Grootendorst, Hollis, Levine, Pogge, and Edwards (2011) point out, the most notable current feature of pharmaceutical innovation is the huge “drought” in the development of new products.

And the proposal is a controversial one:

we could either treat Stage II and III clinical trials as public goods (where the task would be financed by National Institutes of Health, who would accept bids from firms to carry out this work) or by allowing the commercialization of new drugs—at regulated prices equal to the economic costs of drugs—if they satisfy the Food and Drug Administration requirements for safety even if they do not yet satisfy the current (overly demanding) requisites for proving efficacy.

The last sentence sounds far from what should be a "fair" regulatory process in pharmaceuticals. Anyway, it seems that we have entered in a new perspective on patents and more scholars will be supporting it in the future.  I'm close to this perspective, but the details are important, as usual.

El pensament il·lusori sobre els preus de les teràpies genètiques

Sources of Innovation in Gene Therapies — Approaches to Achieving Affordable Prices

Miro el NEJM  i em trobo un article sobre com pagar la innovació farmacèutica que ve, tema molt important del que no s'en parla prou. I allà es recorda el seu origen: 

All gene therapies approved in the United States thus far have their origins in academic institutions or spinoffs from such institutions that developed indispensable know-how and underlying forms of  technology

 I també recorda l'alt preu pagat per l'adquisició d'aquestes noves empreses amb l'expectativa de preus desorbitats.

Pharmaceutical manufacturers have actively participated in latest age clinical development and testing of the approved gene therapies, and a few have played major roles in expanding the market for these therapies, often by buying smaller companies. The costs associated with these acquisitions and licensing agreements can be very high. For example, Gilead was reported to have acquired Kite Pharma (which had rights to axicabtagene ciloleucel and brexucabtagene autoleucel) for $11.9 billion, and Novartis acquired AveXis (which had rights to onasemnogene abeparvovec) for $8.7 billion. The costs of such intellectual property are largely driven by the absence of limits on drug prices in the U.S. market. The resulting high prices can impose an enormous acute financial burden on patients and payers.

I després explica què fer. Una primera opció seria produir acadèmicament teràpies genètiques. L'exemple CAR-T ens sonarà familiar, i cita Suïssa però s'oblida l'Hospital Clínic i de l'Hospital de Sant Pau:

 The cost to produce tisagenlecleucel, for example, was estimated at approximately $70,000 — a fraction of the therapy’s current prices in the United States and Europe. One approach would be for academic and other research institutions to conduct or contract out late-stage development activities — such as managing clinical trials, corresponding with and submitting applications to the FDA, and manufacturing — for publicly funded treatments that they discover. University hospitals in Switzerland have formed an alliance to manufacture gene therapies in-house to reduce costs and improve accessibility.

L'altra opció seria, llicenciar:

 Regulators and policymakers could encourage institutions that receive federal funding to engage in nonexclusive licensing for certain key platform innovations that are part of the gene-therapy processes they have developed, in keeping with their mission and in recognition of the public funding that supports such discoveries. Licensing to multiple manufacturers would spur competition, which could help improve the technology over time and contain treatment prices.

I la tercera, compra conjunta

A third approach would be to facilitate systemwide price negotiation for gene therapies. In industrialized countries that have mechanisms for drug-price negotiation, prices for such therapies are high but still generally lower than prices in the United States 

Més que opcions possiblement són desitjos. La darrera seria la mesura més definitiva de totes.  Les multinacionals són globals, els mercats locals. Però tot i així ens enfrontaríem a gestionar amb transparència la discriminació de preus per part dels pagadors i reguladors. Implica un govern planetari inexistent, i si existís potser l'altra part no voldria negociar...

En definitiva, d'això s'en diu "wishful thinking", pensament il·lusori. D'il·lusió també en viu el NEJM.

Imatge per guardar i ensenyar quan calgui explicar d'on venen les innovacions...

PD. Fa uns cinc anys vaig fer una conferència on vaig explicar com la farmàcia hospitalària s'enfrontava a un canvi en la funció de producció. I aquest canvi seria provocat inicialment pel receptor antígen quimèric per a les cèl·lules T, CAR-T. Es van sorprendre força. Els temps passa i confirma el que vaig dir. El que sorprèn és que no s'hagi formalitzat com a tal aquest canvi i no es plantegi un canvi organitzatiu profund on s'analitzin les economies d'escala i aprenentatge possibles.

Exposició a Barcelona

Raonable i necessari

Aquesta vegada el Journal of Economic Perspectives ve carregat de valent. Molts temes d'interès relacionats amb la salut.
Avui em referiré a l'article d'en Chandra, Jena i Skinner sobre efectivitat comparada. El text s'ha de llegir sencer i destacaria l'elevada expectativa que dispositen en l'avaluació de l'efectivitat comparada malgrat no hi hagi cost-efectivitat. Comparteixo totalment la seva perspectiva.
Aquesta és la seva posició:

We argue that comparative effectiveness research still holds promise. First, it sidesteps one problem facing cost-effectiveness analysis—the widespread political resistance to the idea of using prices in health care. Such resistance is not just from political interest groups, but also from voters, who even in lab settings often dislike rationing based on cost effectiveness (Nord, Richardson, Street, Kuhse, and Singer, 1995). Second, there is little or no evidence on comparative effectiveness for a vast array of treatments: for example, we don’t know whether proton-beam therapy, a very expensive treatment for prostate cancer (which requires building a cyclotron and a facility the size of a football fifi eld) offers any advantage over conventional approaches. Most drug studies compare new drugs to placebos, rather than “headto- head” with other drugs on the market, leaving a vacuum as to which drug works best (Nathan, 2010). Simply knowing what works and what doesn’t will improve productive effifi ciency by shedding medical practices that are unsafe at any price.

Aquí no tenim ni això encara que la llei tímidament demana avaluar utilitat terapèutica i ningú es preocupa per ara d'aplicar-la. Cal trobar un patró per mesurar aquelles prestacions que són raonables i necessàries.

Pharma industry regulation: extracting or creating value

 The Global Pharmaceutical Industry. The Demise and the Path to Recovery

The pharmaceutical industry has reached a tipping point. Its business growth is predicated upon fagrantly raising drug prices (especially in the U.S.), thereby increasing the inability of patients to afford medications. The clinical trials that provide the basis for pharma’s new drug development rely on biased designs to favor approvable outcomes, even as sponsors selectively publish mainly the reports that contain favorable results for their test drugs. The industry’s research process exerts a corrupting infuence on medical researchers and the channels of medical communication, while its everyday product promotions involve regular payments of financial and other inducements to prescribers that effectively constitute bribes. Even its involvement in continuing medical education poses a confict of interest and a corrupting infuence on medical practitioners.

If pharma continues operating in this manner, it cannot complain when citizens worldwide demand their governments impose onerous restrictions. Each passing week sees the emergence of additional outrages that make such controls more likely.

Any generalization doesn't fit with an objective observation of reality. However, in chapter 5, you'll find proposals for a new regulation.  

La teranyina que sosté la financialització dels medicaments, la salut i la vida (2)

 Sick with “Shareholder Value”: US Pharma’s Financialized Business Model During the Pandemic

Als USA, la Inflation Reduction Act ha obert la caixa dels trons. La possibilitat que el govern pugui negociar els preus dels medicaments finançats públicament ha desesperat a la indústria que ha engegat una campanya de lobby inusual. Es tracta de protegir els preus alts perquè altrament no hi haurà innovació, això diuen. Però malgrat aquesta campanya, fa pocs dies el WP ja deia que no se n'han sortit i que estem propers a grans canvis, que es resumeixen en aquests 6:

1) Drug price negotiation

2) A cap on out-of-pocket spending

3) Lower prices for insulin

4) Free vaccines

5) Inflation penalty for drug manufacturers. 

6) Extra help for the most vulnerable

El govern vol estalviar fins a 100.000 milions $ en aquests propers anys. I destacaria especialment, això de que si volen augmentar el preu més que la inflació (d'aquells medicaments ja en el mercat) hauran de fer descomptes al finançador públic. Dissuasió per tant de provocar preus excessius.

I aquí és on entra Wall Street que ho rebutja de dalt a baix i que ho veu com una amenaça al model de financialització que ha funcionat fins ara. Diuen que fins a 100 medicaments ja no arribaran al mercat. I aquesta amenaça no creïble no és certa perquè sabem això:

Data for the 474 corporations included in the S&P 500 Index in January 2022 and publicly traded from 2012 through 2021 reveal that these corporations distributed $5.7 trillion as share repurchases during the 2012-2021 fiscal years, representing 55 percent of net income, and $4.2 trillion as dividends, an additional 41 percent of net income.

Les recompres d'accions a la borsa per part de les companyies són un 13% superiors al que dediquen a la innovació.

As shown in Table 1, for the decade 2012-2021, distributions to shareholders by the 14 pharmaceutical companies that were among the 474 S&P 500 companies in the database represented 110 percent of net income,7 a larger proportion than the highly financialized 96 percent for all 474 companies. At 55 percent, the stock buybacks of the subset of pharmaceutical companies was the same proportion of net income as the 474 companies, but, at 54 percent versus 41 percent, pharmaceutical dividends as a proportion of net income far exceeded that of all the companies in the dataset. The 14 pharmaceutical companies accounted for 3.1 percent of the revenues of all 474 companies but 6.6 percent of the net income, 6.6 percent of the buybacks, and 8.8 percent of the dividends. The $747 billion that the pharmaceutical companies distributed to shareholders was 13 percent greater than the $660 billion that these corporations expended on research & development over the decade.

En aquest article de Lazonick hi trobareu molts més detalls sobre com ha canviat el model de negoci amb la biotecnologia. Si amb el model anterior el paper de la borsa era el típic de separació de propietat-control, en el nou les opas eren la forma de control per part de fons de capital-risc i després el paper del NASDAQ va oferir opcions d'entrada i sortida que abans no existien. L'article ho explica magníficament, no ho he vist enlloc més. La interacció de les recompres d'accions amb retribució escandalosa als directius de les companyies farmacèutiques esdevé una cosa mai vista a cap altra indústria.

Any 2021, el màxim directiu de Regeneron va ingressar 452 milions de $. No cal dir res més, tota la taula és una desmesura.

Què cal fer segons Lazonick?. El canvi en la regulació de preus és només el primer pas. Cal prohibir la recompra d'accions, deslligar el pagament dels directius dels valors de l'acció a borsa, posar representants dels accionistes al consell, reformar la fiscalitat de les empreses, encoratjar carreres professionals. 

Molta feina per endavant si es vol capgirar la tendència de financialització dels medicaments que vivim. Altrament, un avís, tot el que als USA es disminueixi com ingressos, voldran que sigui compensat amb fons provinents d'altres països. Per tant cal estar alerta als moviments propers i avançar-se als esdeveniments.

 

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.

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!

Overvaluing expensive drugs

A research from University of York has concluded that NICE is overvaluing expensive treatments because its cost threshold - the price at which a treatment is deemed good value for the NHS - is set too high. The threshold value per quality-adjusted life year (QALY) - a measure of the health benefits of a treatment - should be lowered from £30,000 to just £18,317, their analysis found. It suggests the NHS may be wasting money on treatments that are not as good value as first thought. Professor Sculped said:

It is crucial that the cost effectiveness threshold is seen as representing health forgone as the additional costs of new technologies are imposed on the fixed budgets of local commissioners. For decisions made by NICE and many policy options considered by the NHS and DH, this is the key to establishing the value for money of new services.

This is a strong criticism against QALYs, let's see if it has some impact in the near future. Fortunately, the British have the opportunity to debate on it. Nearer here, the press is saying now that 30% of drugs requested for approval were rejected (7 out of 24). No details available, no website, no transparent process. That's alleged democracy, southern style. NTA=Nothing to add.

PS. If you don't want to read the article, have a look at this presentation. I suggest you save it, it may be useful for the future.

PS. As you can see from my blog, in one week, two officials have said different numbers of rejected drugs for public funding (2 vs 7). Does this make any sense? Is there anybody asking for an explanation in Parliament?

PS. Follow the controversy on DSM-5 at BBC News.

PS. Check here how our drug prices have converged to the european average.

PS. Must read: Uwe Reinhardt blog.

PS. Interesting article on 20 years of economic evaluations of cancer.