Tag: Pfizer

Food for Thought: It’s becoming a habit – IQWiG takes approval studies apart

Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) this year put out several negative assessments of newly introduced drugs, stating the data did not prove “additional benefit” over existing treatments. In all cases, IQWiG came to the conclusion after deviating from the study design the companies had discussed with the regulators. Instead, IQWiG’s experts divided the patient population into subgroups, saying those subgroups needed different comparator treatments. As a result, these data were either not available or the subgroups were too small to demonstrate statistical significance.

One example is Pfizer’s Xiapex injectable collagenase, approved in early 2011 to treat Dupuytren’s contracture. IQWiG stated that Xiapex does not provide an additional benefit to patients because “it was not possible to derive such additional benefit from the dossier and because the manufacturer did not provide additional or suitable data” to substantiate the claim.

While the manufacturer had compared the Xiapex injection to a surgical treatment, partial fasciectomy (PF), IQWiG for its assessment established six subgroups of patients according to the severity of the disease and chose three different treatment options as comparator: no therapy, percutaneous needle fasciectomy (PNF) and partial fasciectomy (PF). As a result, IQWiG was able to state that Pfizer did not provide evaluable data because the company’s selected comparators differed from IQWiG’s comparators for all but one patient subgroup.

In the case of Eisai’s breast cancer drug Halaven eribulin, IQWiG’s verdict ruled that it could not find evidence for eribulin resulting in a prolonged life expectancy. IQWiG added that Halaven might provide an overall survival benefit for patients for whom taxanes or anthracyclines are no longer an option, but it was unclear whether the benefit was significant. Again, the assessment was made by subdividing the patient group. IQWig defined two subpopulations – one for which an additional anthracycline or taxane treatment was thought to be an option and one for which this was not.

Eisai, in contrast, had compared Halaven to a “Treatment of Physician’s Choice” (TPC) as there are no established national or international treatment guidelines for a standard therapy of women with metastatic or locally advanced breast cancer after failure of two standard chemotherapies including an anthracycline or taxane. This design of Eisai’s EMBRACE was established in discussions with the European Medicine’s Agency (EMA). Being a European study, the participating physicians sometimes opted for therapies not approved in Germany – a reason for IQWiG to not include these data in its assessment. As a result, only 69% of the EMBRACE study patients were regarded as suitable for an assessment.

The same approach was taken in the assessment of Novartis’ Gilenya fingolimod, the first oral treatment for Multiple Sclerosis (MS) approved in 2011. IQWiG once again performed separate assessments of the drug in three groups of patients, choosing three different comparators. Following this operation, IQWiG was able to find data only for one of these subgroups in the study, not enough to establish an additional benefit with sufficient statistical significance. However, one of the comparisons chosen by IQWiG – fingolimod against glatiramer acetate in patients with relapsing/remitting MS – would have been impossible as fingolimod is approved as second-line therapy in this indication while there are no studies of glatiramer acetate differentiating between first-line and second-line treatments.

In all cases, manufacturers may respond to the assessment, after which the Federal Joint Committee (G-BA) will review IQWiG’s recommendation before making a final decision.  If G-BA deviates from IQWiG’s negative assessment, the manufacturers have to negotiate the price with the Statutory Health Insurance Funds Association (GKV-Spitzenverband) under the AMNOG pricing scheme. If G-BA agrees with the IQWiG assessment that a drug has no clinical benefit beyond available treatments, the drug will be added to the reference pricing system, which gives the same base price to all comparable drugs in the respective therapeutic group.

Food for Thought: Weekly Wrap-Up

The EHEC epidemic in Germany with 4,300 patients and 50 deaths has changed the way public health institutions will deal with future epidemics, writes Christina Hucklenbroich in Frankfurter Allgemeine Zeitung (FAZ). She cites microbiologists involved in the rapid sequencing of the EHEC strain who think that the epidemic gave birth to the new discipline of “prospective genomic epidemiology”. To date, sequencing has been performed retrospectively only. However, using the novel Ion Torrent PGM HGS platform, scientists from the University of Münster were able to sequence the EHEC strain responsible for the outbreak within 62 hours. The scientists now think of a software generating a plain language report interpreting the genome and analyzing for toxins and antibiotics resistances of the germ in question so that immediate therapeutic and prophylactic consequences are possible.

Gas, electricity and hydrogen from algae are in the focus of a story by Susanne Kutter in Wirtschaftswoche. She features Sven Kerzenmacher and Johannes Gescher from the University of Freiburg and their efforts to produce electrical current directly from bacteria. The technology is based on the Shewanella bacterium which can transfer electrons generated by breakdown of sugar or other nutrients from the cell surface to conductive materials. Shewanella lives in fresh-, brack- and seawater and thrives on organic waste. The researchers are now trying to design a Shewanella-based mini-powerplant the size of a refrigerator which is able to produce 5-10 Watts of electricity per day – sufficient to meet the demand of a four-person household. Among others, Kutter also features a dual-chamber solar module developed by researchers from Leipzig, Karlsruhe and Bremen. In the first chamber, algae are forced by an excess of oxygen to produce hydrocarbons (“photorespiration”). The hydrocarbons enter the second chamber via a membrane and are used by bacteria to produce methane under anaerobic conditions. Readers interested in learning more about Shewanella may find regular updates on Shewanella Blogger.

While algae seem to be an ideal biofuel replacement for gasoline in the first place, it has turned out that the economics is a problem, writes Erica Gies in Forbes. Gies revisits former biofuel-from-algae startups that are now turning to more profitable products, using “green” chemistry to replace petrochemicals or unsustainable bio-based oils.

Also in Forbes, Matthew Herper deals with an op-ed in Nature Reviews Drug Discovery by John L. LaMattina, ex-CEO of Pfizer, Inc. LaMattina writes the pharma’s M&A activities have had a “devastating” effect of research and development efforts which will impact the industry over the next decade. The comment is all the more telling as LaMattina was pivotal in Pfizer’s acquisitions of Warner-Lambert, Pharmacia, Wyeth and many other companies. LaMattina summarizes that the consolidation by M&A led to fewer companies pursuing novel ideas and disruptions in research processes. Friction is caused, among others, by the need to streamline computer systems, procedures to track side-effects and others. Usually, a merger delays the start of any new research project by nine months. LaMattina’s comment can be accessed here.

Brandon Keim in Wired explains that most genetic differences in people are not caused by mutations but by variations in the genome’s architecture. At present, sequencing is designed to identify SNPs and as every sequencing method is breaking down the DNA in smaller pieces most genomic studies a blind to larger variations. First sequencing studies looking at larger DNA pieces now revealed that individuals seem to be distinguished less by their SNPs than by their structural variations, i.e. wholesale duplications and reversals, or unexpected additions and omissions of long DNA sequences.

Finally, Catherine de Lange in the New Scientist features the first car plugging into the driver’s brain to cut response times in case the car needs to stop suddenly. The invention of Stefan Haufe from the Berlin Institute of Technology uses an EEG headset and sensors on the leg to detect neuronal patterns and muscle tension to find out that the driver intends to apply the brakes. The system improves response times by 130 milliseconds which translates into the length of a small car when stopping from a speed of 100 km/h.

Food for Thought: Weekly Wrap-Up

First signs of future onset of Alzheimer’s disease (AD) can be found already at the age of 14, reports Volker Stollorz in Frankfurter Allgemeine Sonntagszeitung (FAS). Introducing findings by Heiko Braak and Kelly del Tredici from Ulm University, he also points out that AD seems to originate in the Nucleus coeruleus region of the brain stem from which the typical AD clots slowly spread alongside nerve tracts. Stollorz features plans to include members of families with hereditary forms of AD in future clinical trials to test preventive drugs and treatments. Researchers in Germany currently are planning to launch a website and to found a network modeled according to the US “Dominant Inherited Alzheimer Network” (DIAN). Stollorz and his colleague Thomas Liesen also are co-authors of a TV documentary which can be found here for four weeks from July 19, 2011.

Jutta Hoffritz in Die Zeit reports on novel anticoagulants, e.g. Pradaxa by Boehringer Ingelheim, which is already marketed in the US, and similar drugs developed by Bayer Schering, Pfizer and Daiichi Sankyo. The drugs are developed to replace marcumar which carries the risk of severe side effects and is difficult to dose. However, while the new drugs show better efficacy and promise better compliance, Hoffritz cites German medical doctors expressing skepticism because of unknown long term risks and the anticipated high pricing of the drug. Ulrich Schwabe, editor of Arzneiverordnungsreport, a publication known to be very critical about the pharma industry, is quoted with the calculation that treating all eligible patients in Germany with Pradaxa would amount EUR 4.9 billion per year. The calculation is based on the price of the current daily dosis as the drug is already marketed in Germany for the prevention of thrombosis prior to knee and hip replacement surgery.

Christian Heinrich also in Die Zeit features a trend among pharma companies to search for potential applications of their already approved drugs. As an example, he introduces the “Common Mechanism Research” department of Bayer Schering AG, which is systematically studying unusual effects of Bayer compounds to find clues for novel therapeutic applications. Well-known examples of dual use compounds are sildenafil, which was originally developed to treat circulatory disturbance of the heart (now a common drug to treat erectile dysfunction), and aspirin, which was known as a pain killer and only later developed as anti-coagulant.

Christina Hucklenbroich in Frankfurter Allgemeine Zeitung (FAZ) reports on the suspicion that recently observed deaths of cattle in Germany may be caused by Clostridium botulinum bacteria. However, she points out the the jury is still out on whether there is a novel zoonosis called chronic botulism as presence of the toxin in minute amounts in the gut of affected animals is difficult to confirm. In addition, the source of the bacteria detected in some animals has not yet been identified.

Also in FAZ, Hildegard Kaulen reports on novel findings how smoking cigarettes suppresses appetite. Researchers from Yale University, she writes, found a hitherto neglected nicotine receptor in the brain, which influences the neuronal circuit involved in appetite regulation. Once nicotine binds to the receptor, the nerve cells start releasing the neurotransmitter POMC which in turn influences nerve cells regulating satiety feelings.

Nicholas Wade in The New York Times reports on efforts by scientists from Harvard Medical School to introduce hundreds of changes in the genome of E. coli bacteria simultaneously, an effort dubbed by a colleague as as “macho molecular biotechnology”. The alteration of 314 sites is just an intermediate step by George M. Church and Farren J. Isaacs to establish a method by which certain stretches of DNA could be changed just the way a word processor searches and replaces certain words in an entire document in one step. The researchers removed a particular stop codon (T-A-G, or “amber”) and replaced it by another (which works just as well). Now they are planning to also remove the gene recognizing the deleted stop codon and subsequently to reintroduce amber and reassign it a new function, e.g. to incorporate a novel amino acid into the bacterium’s proteins.

The Economist announces the world’s first  “World Cell Race” taking place in August. Cells sent in by various research institutions all over the world will compete against each other in the race to move towards a chemoattractant. The scientists thereby hope to identify genes involved in cell mobility which are known to be important drivers in cancer metastasis as well as wound healing and immune responses.

New Scientist recently featured a series of articles dealing with bacteria (“bugs that break all rules”): Caroline Williams introduces multicellular behavior of socializing bacteria, features bugs that hunt in packs, bacteria large enough to be visible with the naked eye and bacteria with backbones and cell compartments.

And finally, Cinthia Briseno in Der Spiegel reports on studies proving that the internet is changing the way we memorize and learn. The ability to rely on the internet seems to encourage people to make less mental notes of facts they are sure to find in the web with a few keystrokes.

Food for Thought: Weekly Wrap-Up

Sascha Karberg in Frankfurter Allgemeine Sonntagszeitung (FAS) features the latests attempts of biologists to understand and replicate the endosymbiosis of cyanobacteria and cells of eucaryotes that led to the chloroplasts found in all green plants. Already in the 1970s, biologists successfully incorporated cyanobacteria into an amoeba and meanwhile, several animals carrying endosymbionts providing them with extra energy from the sun have been discovered. This is now replicated in the lab. Using genetically engineered cyanobacteria, scientist recently created zebrafish larvae as well as mice and hamster cells with endosymbionts that not only survive but replicate. Karberg also explains why this will not lead to green cows living on sunlight.

Silvia von der Weiden in Die Welt introduces novel findings about the role of water molecules in protecting and maintaining the DNA geometry. Reducing or expanding the size of the water sheath covering the DNA changes the conformation of the molecule as if activating a switch. The findings may be used to create novel DNA-based nanotools or develop DNA-binding drugs to influence gene activation.

In Forbes, Mattew Herper features a graph proving Moore’s law wrong – at least in the decline of cost of DNA sequencing: the cost of getting DNA data (i.e. cost per genome as well as per megabyte of DNA sequence) is dropping way faster than the cost of processing data on computers. In a separate article, Herper endorses Wall Street’s forecast, that Pfizer’s Prevnar 13 vaccine against pneumococcus infections will be the company’s biggest seller in five years.

The Economist features an Italian engineering firm developing a system to collect oil spills in the sea that is based on wool. Already the company has been granted a patent of its containerized, ship-based kit. After absorbing the oil, the wool is pressed to recover the oil and the reused.

Andrew Pollack in the New York Times reports about setbacks in the development of treatments based on stem cells. Experiments recently  showed that induced pluripotent stem cells – which are thought to be superior both ethically and technically to embryonic stem cells – are rejected by the immune system. However, it is not yet clear whether the results obtained in mice hold true for humans, too.

 

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