Tag: G-BA

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: IQWiG Says Benefit Of Ezetimibe Not Proven

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.

Food for Thought: Weekly Wrap-Up

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 Scientist reports. 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.

Food for Thought: Future Reimbursement of Novel Cancer Drugs in Germany

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.

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