Tag: myocardial infarction

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

Hearts can heal themselves, at least in newborn mice, reports  Sindya N. Bhando in the New York Times. She features a research group that is now trying to identify the genes regulating the process. If the researchers could restart the genetic network in adult animals, science would be a step closer to a better heart disease therapy.

Matthew Herper in Forbes deals with the success of Vertex’s cystic fibrosis drug VX-770 in its 161 patients STRIVE clinical trial. While it works only in a small subset of patients carrying a particular mutation, in this group it improved the patients’ ability to exhale by about 17%. Robert Langreth, also in Forbes, introduces biotech investor Randal J. Kirk who made more than $2 billion from his biotech investments, among others, by selling New River Pharmaceuticals to Shire. Right now, he is about selling his anti-depressant play Clinical Data to Forest Laboratories. Kirk prefers to buy unknown companies at a very low price and stays until a drug gets to the market. His latest interest focuses on synthetic biology, and he runs and finances the 180-person company  Intrexon, founded in 1998 by biologist Thomas Reed. Intrexon claims to command a library of 70,000 DNA pieces that can be used to control gene expression. This enables it, as an example, to induce and regulate in vivo protein expression through dosing of a small molecule activator. Applications range from medical to agricultural and industrial biotechnology and protein production.

Kate McAlpine in New Scientist explains how a technology that manipulates light so that it can deliver sharp images through opaque materials might someday be useful to treat cancer. Like opaque material, human skin scatters light in both time and space, however with the new technology it may be possible to exactly target and destroy cancer cells by laser light without harming surrounding healthy tissue.

Joachim Müller-Jung in Frankfurter Allgemeine Zeitung (FAZ) reports on a new technology to improve hygiene in clinics. Developed by the Max Planck Institute for Extraterrestrial Physics it generates cold plasma gas that is able to kill bacteria even in skin pores within three to five seconds. The technology already is being used in food processing and for treating chronic wounds. The device is about the size of a hand dryer already used in public lavatories. A license to the technology is still available.

Susanne Kutter in Die Wirtschaftswoche reports on a new test to diagnose a myocardial infarction on the spot. It is based on the enzyme glycogen-phosphorylase BB which is released into the blood stream as soon as the heart muscle is suffering from oxygen deprivation. A common competitor test on the market is based on a molecule released only after disintegration of heart muscles cells and tissue, i.e. hours after the incident. The Diacordon test is marketed by Diagenics.