Various studies have demonstrated that lowering cholesterol levels with statins is preventing heart attacks and other cardiovascular complications. However, some patients do not tolerate statins or do not achieve recommended cholesterol levels with statins alone. These patients often are prescribed ezetimibe (sold as Ezetrol by MSD Sharp & Dohme in Germany), an oral cholesterol-absorption inhibitor, either alone or in combination with statins. A fixed combination of ezetimibe with statin simvastatin is sold as Inegy.
Last year, Germany’s Federal Joint Committee (G-BA) which is deciding about drug reimbursements for the country’s statutory healthcare system, commissioned Germany’s cost-benefit watchdog IQWiG to assess the benefit of ezetimibe either alone or as combination therapy.
IQWiG published its report earlier this month. While it not disputes that ezetimibe is lowering cholesterol levels, the institute states in its report that it has been unable to identify any review or study demonstrating that the prescription of ezetimibe alone or in combination does provide patient-related benefits in terms of reducing “all-cause” or “vascular” mortality.
However, new data and findings supporting the benefit of ezetimibe will be available soon. Pulse Magazine, a leading medical weekly in the UK, reported Sept. 2 that researchers looked into the effectiveness of ezetimibe in combination with statins on all-cause mortality over a period of 4.3 years. They concluded that the combination treatment – if used after a myocardial infarction – resulted in a 55% decrease in all-cause mortality compared to patients taking simvastatin alone. The trial was a retrospective study on a cohort of nearly 15,000 patients from the UK’s General Practice Research Database. The researchers already had announced a presentation of the results at the European Society of Cardiology Congress in Paris end of August, but cancelled the presentation to perform a more complex analysis of the data.
Galantamine and transdermal rivastigmine plaster can delay loss of cognitive function in Alzheimer’s disease (AD) patients, Germany’s Institute for Quality and Efficacy in Health Care (IQWiG) said in a preliminary report published on its website. In 2007, IQWiG had issued a negative report on the benefit of donezepil, galantamine and rivastigmine, however in 2009 the institute initiated an update, adding additional published and unpublished studies for the appraisal of galantamine and including the rivastigmine plaster which entered the German market in 2007.
IQWiG now states that galantamine at higher doses has a positive effect on cogitation and retentiveness of female patients with mild and moderate AD. However, it added that there was no evidence of improvement of daily routine abilities or psychopathological symptoms such as unrest and depression in both male and female patients. In addition, IQWiG notes that patients often dropped out of the study because of side effects such as nausea, vomitus or diarrhea. It also states that it did not find evidence supporting a galantamine treatment for more than 12 months.
For the rivastigmine plaster, IQWiG said it found hints that the 10 square centimeter plaster improves cognition of patients under 75 years of age; however it states that the data were not resilient enough to support an assessment as “proof of efficacy.”
IQWiG said that both manufacturers, the pharma companies Janssen-Cilag and Novartis, provided all study data requested by IQWiG, including unpublished data comprising 48% of study patients. Juergen Windeler, head of IQWiG said in a statement that this was further underlining the necessity to introduce mandatory publication of clinical study data.
The human genome of newborns contains an unexpectedly low number of mutations, writes Joachim Müller-Jung in Frankfurter Allgemeine Zeitung (FAZ). Contrary to earlier estimates of 100-200 mutations generated in the germ cells of parents, the number is only about 60. Results come from sequencing the entire genomes of two families with one child each. The results have implications for understanding human evolution and genetics.
Sonja Kastilian, also in FAZ, features a preliminary report of IQWiG, Germany’s watchdog agency appraising drugs and treatments for quality and cost effectiveness, on the benefits of HPV testing of women as a screening for ovarian cancer. IQWiG set out to compare DNA tests for HPV with common pap smear tests and reported that the HPV tests leas to an earlier diagnosis and better follow-up examinations, regardlesss of whether it is applied alone or in combination with the conventional test. A final decision on whether the test is to be reimbursed by Germany’s statutory healthcare system is expected for 2012. In 2006, the Joint Federal Committee (G-BA), the body in charge, had voted against reimbursement for cost reasons. Kastilian also points out that HPV vaccination rates at present are below 30% in young women in Germany, in contrast to up to 81% in the UK, Portugal, and Australia. Reason has been an unduly discussion in German media about potential risks, high costs and lack of efficacy.
Uta Neubauer in Neue Zürcher Zeitung (NZZ) reports on novel approaches to use cold plasma to disinfect wounds, hands, and food. A method and device developed by the German Max Planck Institute for Extraterrestrial Physics has already demonstrated safety and efficacy in treating wounds and disinfecting hands. At present, it is under investigation for the treatment of foods, e.g. food additives and berries.
Sven Titz, also in NZZ, deals with latest insights into the physics of the water surface. Using vibration spectroscopy, physicists of the University of Southern California at Los Angeles found that the surface is made up basically by -OH groups of the water molecules sticking out from the liquid. The discovery will lead to better understanding solubility of molecules in water.
Forbes this week introduces two innovations in optics. Jennifer Hicks writes about the “socialization of the microscope” by a technology that allows the display of microscopic images on an extremely large multitouch screen, just like an oversized iPad. Thereby, groups of students, pathologists or researchers can focus on tiny details by touching, gesturing, and zooming in and out. A video of the microscope at work can be found here.
Californian-based start-up Lytro has unveiled a camera that can take pictures without focusing, writes Tomio Geron in Forbes. Instead, focusing on any point of interest in the photo is done once the image is loaded on a computer. The consumer camera is based on the light field technology invented by Stanford University researchers. The camera is fitted with special lenses and a sensor that captures every ray of light hitting it, regardless of whether it is from the fore- or the background, and records its individual color, intensity and direction. The camera therefore also can be used to generate 3D-pictures. Examples can be found here.
The Economist this week introduces an intelligent drug delivery approach using nanoparticles. It can be used to deliver anti-cancer chemotherapeutic drugs and makes use of the blood-clotting mechanism: first, nano-sized golden rods are injected into the blood stream. They fit into the unusual pores common in capillaries nourishing tumors and thereby mark tumor sites. Once they are in place, the tumor site is treated with laser light bursts. Their energy is absorbed by the gold and converted to heat destroying the capillaries so that the body’s coagulation system is triggered to repair the damage. This is when the second nanoparticles come into play. They carry the chemotherapeutics together with a fibrin-binding protein fragment and are designed to release the drug upon fibrin-binding only. The treatment strategy therefore delivers the drug exactly to the site the coagulation system is active, that is, at the tumor. The method developed at the Massachusetts Institute of Technology (MIT) has proven safety and efficacy in mice and will be tested in humans soon.
Researchers from the University of Rochester have come up with just another idea to release drugs on target, the New Scientistreports. They found that nanocarbon tubes containing aqueous solutions can be made to pop open by heating them from the outside with infrared lasers. Patients could be administered nanocontainers carrying drugs to deliver it to a desired target where the drug then is released by laser light.
And finally, Die Welt this week deals with wrinkles and high tech attempts to avoid or get rid of them. Clinical studies in people with an average age of 87 prove that vitamin A1 (retinol) is useful to smooth skin. Also, light from LEDs is able to remove a water film caging the skin’s elastic fibers so that they become rigid. The method is best applied by pre-treating the skin with green tee polyphenols to deactivate free radicals generated by the LEDs. Moreover, scientists from Hamburg-based Skin Investigation and Technology SIT found out that eating one bar of dark chocolate a day also leads to a 34% improvement of skin elasticity after 6 months. Further attempts to eliminate wrinkles are being made by using signaling peptides activating collagen-producing cells and by polymers carrying nanoparticles that are injected between outer and inner skin layers. The resulting films disperse the compression forces within the skin, thereby “ironing” it from inside.
Germany’s new law regulating the reimbursement of drugs, the so-called Arzneimittelmarktneuordnungsgesetz – AMNOG, requires companies planning to introduce a novel drug to the German market to provide a value dossier, if they want reimbursement of the full price for the first year of marketing (See the akampioneer, “Germany’s New Reimbursement Law“). This value dossier not only needs to demonstrate efficacy and safety, but also has to provide evidence that the drug is more advantageous to existing treatments in terms of patient-relevant endpoints such as morbidity, mortality and quality of life.
This is difficult to prove as many novel cancer drugs are approved on the basis of surrogate endpoints such as slowing or stopping cancer growth (objective response rate ORR, time to tumor progression TTP, time to treatment failure TTF or progression-free survival PFS).
Late last month, Germany‘s Institute for Quality and Efficiency in Health Care (IQWiG) has published details on how it is going to evaluate the patient benefit in these cases. IQWiG usually is evaluating drugs on behalf of the so-called Gemeinsamer Bundesausschuss G-BA (Federal Committee), a decision body within Germany´s statutory healthcare system.
In cancer, IQWiG plans to primarily address „the question as to whether a therapy can prolong the life of affected patients. In addition, a new therapy should alleviate symptoms, prevent complications, and improve quality of life.“ If surrogate endpoints have been used for approval, IQWiG will only accept them as evidence for patient benefit, if the validity of these endpoints for demonstrating patient benefit can be proven by correlation-based approaches based on randomized controlled trials.
In a 160 page „rapid report“ (available in German only) IQWiG details its approach to search available literature for studies on the correlation between surrogate and patient-relevant endpoints. In addition, it describes how it is performing a meta-analysis of these studies for assessing the strength of the correlation (three levels) and the reliability of the validation studies (four levels) to reach an overall conclusion about the validity of the surrogate endpoint for a decision whether the new drug is providing patient benefit.
While the institute so far has only differentiated between „proof“ of surrogate endpoint validity and „indication“ of validity (meaning medium reliability), it proposes to introduce a third category called „hint“ for the fulfillment of certain minimal requirements for the available studies. This category will be applied in cases where the validity of a surrogate endpoint is unclear – a situation IQWiG expects to be quite common. In these cases, IQWiG states, „it can also be taken into account how strong the effect of a treatment turns out to be“. IQWiG would then seek to find a threshold value for the surrogate marker and evaluate whether the new treatment exceeds this value, e.g. whether it decelerates tumor growth for longer than a specified period of time.
Last not least, IQWiG appeals to drug makers and study groups to make accessible their analyses on the validity of surrogate endpoints and the specification of threshold values, e.g. in special registries.
A short English summary of IQWiG‘s basic assumptions on how to recognize at an early stage whether a new cancer therapy prolongs life can be found here. IQWiGs proposals for the early benefit assessment of cancer drugs can be read, also in English, here.
