Tag: Eli Lilly

Food for Thought: Innovation on Trial

Germany’s new Law on the Reorganization of the Pharmaceutical Market (AMNOG), which came into force January 1 this year, has substantially changed the rules for the introduction of new medicines on the German market. The akampioneer already has reported on the novel regulations and procedures – now it is time to look at the consequences AMNOG has had already.

Since the beginning of 2011, 18 dossiers for the required benefit assessment have been filed with the Federal Joint Committee G-BA, the highest decision-making body of the joint self-government of physicians, dentists, hospitals and health insurance funds in Germany. G-BA is then assessing the “additional patient-related benefit” of a novel drug, either itself or by assigning Germany’s Institute for Quality and Efficacy in Health Care (IQWiG). If G-BA identifies an additional benefit, the umbrella organization for the statutory health insurance funds and the pharmaceutical company negotiate the reimbursement price as a discount on the original selling price within six months. If negotiations fail to reach an agreement, an arbitration commission defines the reimbursement price using the European price level as a standard.

Most cases are still pending. In one of the 18 cases (the statin pitavastatin marketed by Merckle Recordati in Germany) , the manufacturer itself requested the drug to become reimbursed under the fixed price system. In two cases, marketing was halted in Germany by the manufacturer following a negative G-BA assessment: Boehringer Ingelheim and Eli Lilly decided not to market linagliptin, a DPP4 inhibitor for the treatment of type II diabetes; the companies think G-BA chose the wrong therapy for comparison and assessment of the additional benefit.

Novartis removed Rasilamlo from the market, effective September 1. The oral drug is a combination of aliskiren and amlodipine, which was approved in April this year for the treatment of high blood pressure patients not adequately controlled by either aliskiren or amlodipine alone. The company could not get to terms with G-BA on the data required for the assessment of the additional patient-related benefit.

The decision not to market a drug in Germany if the assessment is negative and the setting of a low price is imminent certainly reduces sales; on the other hand it prevents the setting of a lower price in other European countries that use Germany’s drug prices as reference.

The first completed assessment regards AstraZeneca’s platelet aggregation inhibitor ticagrelor, which was approved in December 2010 for the prevention of thrombotic events in patients with acute coronary syndrome or myocardial infarction with ST elevation, and is intended to be used in combination with acetyl salicylic acid (ASS). G-BA had assigned IQWiG with an assessment that deviated from the design of the studies used for approval and from the comparator therapy G-BA originally had agreed upon with the manufacturer. For approval, the drug had been compared to clopidogrel (plus ASS). IQWiG, however, defined subgroups and compared ticagrelor plus ASS with clopidogrel plus ASS in patients with unstable angina pectoris and myocardial infarction (with and without ST elevation) and prasugrel plus ASS as a comparator for patients with ST elevation, which had received a coronary bypass or a percutaneous coronary intervention (PCI) .

As a result, G-BA ruled that the drug has an additional benefit only in patients with myocardial infarction without ST elevation and in patients with unstable angina pectoris. In these cases, G-BA sees a moderate additional benefit. IQWiG had stated that the data provided by the manufacturer to support efficacy in patients with ST elevation did not sufficiently prove additional benefit in this subgroup.

While it certainly is a good idea to ask whether a novel drug not only meets regulatory requirements but also translates into patient benefit, the process of assessing this benefit and the degree of improvement as compared to existing therapies is a mess in Germany.

One important point is transparency. The crucial selection of the comparative therapy for the assessment takes place behind closed doors in G-BA’s pharmaceutical subcommittee. G-BA does not  even disclose the subcommittee’s members – however, it is known that the members are picked from the National Association of Statutory Health Insurance Physicians and from the Statutory Healthcare System. The cheaper the comparative therapy chosen, the bigger is the hurdle to meet the cost/benefit ratio.

Second, as compared to the NICE procedure in the UK as an example, manufacturers are not involved in the process once it has started (except that they may be asked to submit more data), and  if they are not happy with a decision the only possible procedural intervention is taking G-BA to court. Otherwise, they may wait for a year after which they can file an application for submitting novel data – which may be granted by G-BA or not.

Third, it is often very difficult to prove an additional benefit of an innovative medication immediately – except maybe for an antibiotic. Therapies for chronic diseases lead to measurable improvements often in the long or medium run only, and regulatory studies often are not large or long enough to meet the strict “evidence-based” criteria of IQWiG and G-BA. In addition, elderly patients often suffer from multiple diseases, making an assessment even more difficult.

Last not least, for the reference price system the devil is in the details. Will all European countries, including the poor economies of the former communist countries in Southeastern Europe, be included – or only the richer economies of the old European heartland?

All in all, the new regulations already have led to a slowing-down of novel drugs reaching the German market – a development that IQWiG’s new director Juergen Windeler in a recent interview declared as “expected”. He might as well have said “welcomed” as he added that of the about 60,000 drugs on the market in Germany, 95% were dispensable: “Experience shows that good medical care is possible with 2,000 to 3,000 drugs only.”

Food for Thought: Weekly Wrap-Up

Joachim Müller-Jung in Frankfurter Allgemeines Zeitung (FAZ) this week deals with the ethic implications of non-invasive prenatal diagnosis, describing that a huge number of tests based on fetal DNA entering the mother’s blood stream is ready to enter the market. His recommendation is to start an immediate discussion about which tests should be applied and which ones should not.

Ulrich Bahnsen in Die ZEIT interviews Norbert Donner-Banzhoff, Professor at the University of Marburg’s Department of General Practice, Preventive and Rehabilitative Medicine. Donner-Banzhoff conducted a study published in the Canadian Medical Association Journal CMAJ investigating the influence of pharmaceutical advertising on the drug recommendations made in articles in 11 German journals that focus on medical education. Donner-Banzhoff and his team come to the conclusion that journals financed by advertisement from the pharma industry and given away for free almost exclusively recommended the use of specified drugs, whereas journals financed entirely with subscription fees tended to recommend against the use of the same drugs. In the interview, Donner-Banzhoff suggests that a lot of articles published in the free journals have been written by ghost writers and/or members of the pharmaceutical industry.

Matthew Herper in Forbes this week deals with the latest setback in developing drugs to treat Alzheimer’s Disease (AD). He features the failure of Eli Lilly’s semagacest in a Phase III trial in more than 2,600 patients with mild-to-moderate AD. According to an interim analysis, patients receiving the drug, a gamma secretase blocker, worsened to a statistically significant greater degree than those treated with placebo. In addition, the drug was associated with an increased risk of skin cancer. Herper concludes that there is something fundamentally wrong with current hypotheses on the onset of AD and that the failure of the drug may set AD drug development back by many years (see also akampioneer’s recent comment on Probiodrug’s AD hypothesis).

While William Pentland, also in Forbes, reports a potential biofuel breakthrough in producing isobutanol directly from cellulose by using a microbe thriving in decaying grass, Josh Wolfe, co-founder and managing partner of Lux Capital Management, in Forbes states it is time to realize that investing in biofuels may be foolish. He states that while it is hyped as biotech 2.0, there is in fact a fundamental difference to biotech 1.0 which is often overlooked. While biotech 1.0 drugs and molecules can be protected by IP, biofuels cannot. In addition, the marginal cost of producing IP-protected molecules is really low once you did the discovery and first synthesis work (as compared to your margins) – so you can make big profits. Biofuel molecules however have to compete from the onset with the generic fuels already on the market. Biofuel is a commodity, he states, and instead of going back to an agrarian-based economy we should focus on materials and processing based on high energy density, such as uranium.

Donald G. McNeil jr in The New York Times reports on a panel of independent experts from 24 countries that reviewed the handling of the swine flu by the World Health Organization (WHO) in 2009. The draft report – “posted in an obscure corner of the W.H.O.’s Web site” – criticizes the WHO’s “needlessly complex” definition of a pandemic, its inability to deploy 78 million doses donated by rich nations for use in poor ones and its “clumsy communications”.

Colin Barras in New Scientist writes about the origin of cancer and features recent contributions by astrobiologists. While many researchers think that cancer is triggered by a malfunction of the genes trying to control replication which needs to be limited in multicellular organisms, some astrobiologists think a tumor is switching back to some forms of basic cellular cooperation found in the earliest ancestors of multicellular organisms. The distinction is far from being academic: if cancer is some sort of “living fossil” revived it would have only a limited set of survival strategies. In contrast, contemporary medicine regards a tumor as independently evolving cells with nearly unlimited evolutionary potential to escape treatment strategies. The hypothesis explains the co-ordinated survival strategies of cancer, such as angiogenesis and metastasis, and will be further tested soon by genetic profiling.

 

Food for Thought: Weekly Wrap-Up

In Forbes, Matthew Herper this week deals with the failure of Bydureon eventide, the once-a-week anti-diabetes shot developed by Eli Lilly and Amylin Pharmaceuticals. In a head-to-head Phase III trial Bydureon was not superior to Victoza, the once-a-day drug by Novo Nordisk, in terms of lowering blood glucose levels. Both are synthetic versions of glucagon-like peptide-1, or GLP-1. In another article, Herper looks at the biotech busts and breakthroughs of Februay, from KV Pharmaceuticals (shares up 400%) to Orexigen (shares down 64%). Herper concludes that the rejection of the Orexigen drug Contrave by FDA – the third rejection of an obesity drug in a row – “killed the obesity drug field.”

Wired this week features a story by John Timmer who describes experiments, in which the introduction of engineered viruses boost memory recall in rats. The improment is brought about by a viral protein kinase, but the exact mechanism ist still not understood.

In Germany, Sascha Karberg in Frankfurter Allgemeine Zeitung (FAZ) revisits the attempts to cure AIDS by removing the gene for the receptor protein CCRS, which serves as the entry door for the AIDS virus, from the T cells of HIV-infected patients . Humans lacking the CCRS gene show natural resistance to the disease. The genetically modified T cells are then reinjected into the patients’ blood stream (see akampioneer, January 17). In a Phase I trial of this approach by Sangamo Biosciences, preliminary results have been encouraging, leading to a significant and durable increase of CD4+ T- cell counts in the patients.

Magnus Heier in Frankfurter Allgemeines Sonntagszeitung (FAS) deals with the ignorance of medical doctors in Germany regarding therapy guidelines and attempts to solve the problem by publishing patient versions of the guidelines in the internet.

Richard Stone in Sueddeutsche Zeitung (SZ) features an epidemic in Bangladesh caused by the Nipah virus, which was discovered only in 1998. The virus is spread by bats via raw palm tree juice, a delicacy for both bats and humans. Christina Berndt, also in SZ,  deals with the replacement of members in Germany’s federal “German Standing Vaccination Committee” (STIKO) responsible for handing out advice on vaccination practices. Berndt claims that some of the newly appointed members are too close to industry because they participate in vaccine studies sponsored by vaccine manufacturers.

In a five-part series, Kai Kupferschmidt in German weekly magazine Die ZEIT deals with synthetic biology, this week introducing companies developing synthetic fuels and novel ways to produce drugs. Surprisingly, the article does not feature a single German synthetic biology company but US companies only.

Food for Thought: Weekly Wrap-Up

In Frankfurter Allgemeine Zeitung (FAZ), Manfred Lindinger takes up the issue whether nanotechnology poses danger to human health and the environment in an article and an interview with Jochen Flasbarth, president of the German Federal Environment Agency (Umweltbundesamt – UBA). Flasbarth points out that UBA’s nanotechnology study published last year, highlighting gaps in knowledge about potential health hazards, was misunderstood by the media and the public as a sweeping warning of all things nano. He also dismisses calls for introducing a label for products containing nanotechnology: “If there is no risk, we don’t need to put up a warning sign.”

Several German papers feature and discuss an ad-hoc statement on preimplantation diagnosis  issued January 18 by the German National Academy of Sciences Leopoldina and Berlin-Brandenburgische Akademie der Wissenschaften. It was drafted by 13 eminent German academians from biology, medicine, law and philosophy & ethics, among them nobelist Christiane Nuesslein-Volhard. The statement calls for admission of PID under narrowly defined circumstances (high risk of serious monogenic disorder, chromosomal dysfunction, miscarriage or stillbirth). The parliament needs to to regulate PID after the German Federal Supreme Court last year ruled that Germany’s ban on PID was based on misinterpretation of the country’s Embryo Protection Law.

John Tierney in The New York Times provides new insights on people who underwent personal genetic testing to learn about their risk for conditions from obesity to cancer and Alzheimer’s. It is widespread belief among experts and politicians that personal DNA testing needs careful supervision and cannot be offered without expert guidance. The NYT introduces two studies – one follow-up study of about 2,000 people who had a genomewide scan by Navigenics  and one representative sample of 1,500 people – and found that the medical field overestimates the level of psychological anxiety or trauma caused by the results and is way too paternalistic about the tests. One researcher is quoted by saying: “We should recognize that consumers might reasonably want the information for nonmedical reasons. People value it for its own sake, and because they feel more in control of their lives.”

Gardiner Harris reports that the Obama administration has become so concerned about the slowing pace of new drugs coming out of the pharma industry that it has decided to start a federal billion-dollar drug development center. The “National Center for Advancing Translational Sciences” will open in October this year and will beef up early research results by finding leads against new targets or even perform preclinical studies so that projects become attractive to the pharma industry. NIH director Francis S. Collins who is behind the idea, is quoted by NYT as saying: “I am a little frustrated to see how many of the discoveries that do look as though they have therapeutic implications are waiting for the pharmaceutical industry to follow through with them.” In a first step, more than $700 million in research projects from other NIH institutes will be brought together at the new center.

Gina Kolata reports on an FDA advisory committee recommending approval of a new brain scan that can detect the typical plaques in the brains of living Alzheimer disease patients. The test has been developed by Avid Radiopharmaceuticals, now a subsidiary of Eli Lilly (see akampioneer, June 24, 2010).

In the New Scientist, Anil Ananthaswamy features findings from Australian researchers suggesting that Parkinson’s disease, Multiple Sclerosis and maybe other, more common diseases such as rheumatoid arthritis or diabetes, might be cured by antibiotics and subsequent (re-)colonization of the colon with bacteria from healthy people. The hypothesis was derived from case studies of Parkinson’s patients treated for colon infections, in which the treatment also abated the Parkinson’s symptoms. The researchers from the Center of Digestive Diseases in New South Wales are now planning a pilot study in Parkinson’s patients. Already, neuroanatomists from German Ulm University have suggested in 2003 that Parkinson’s might be caused by a bug that breaks through the mucosal barrier of the GI tract and enters the central nervous system via the vagus nerve (Journal of Neural Transmission, DOI: 10.1007/s00702-002-0808-2).

Linda Geddes reports on how cytokines associated with inflammation can enter the brain under certain circumstances and cause depression. Unfortunately, the article fails to mention German biotech company Affectis which already has Cimicoxib, an anti-inflammatory COX-2 inhibitor, in Phase II trials for the treatment of depression, after researchers discovered that COX-2 inhibitors can alleviate depression.