Tag: sildenafil

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.

Update: Germany’s New Drug Reimbursement Law

Germany is about to introduce a new law regulating the reimbursement of drugs within the country’s statutory health care system, and after intense political debates during the second half of 2010, the amended bill (it has the bulky title of “Gesetz zur Neuordnung des Arzneimittelmarktes in der gesetzlichen Krankenversicherung”  – Arzneimittelmarktneuordnungsgesetz – AMNOG) will become effective January 1, 2011. In essence, it puts an end to the free pricing of innovative drugs and expands the reference price system with fixed prices to all drugs regarded as “me-toos”. The law will have consequences for generic producers and drugs already on the market as well, but for biotech companies developing innovative drugs the main challenges are as follows:

“Value”-dossier

Starting next year, companies introducing novel drugs to the German market will have to provide to the statutory health care system a cost-benefit dossier (“value dossier”) parallel to the market introduction, if they want to obtain reimbursement of the full price for the first year. For the dossier, the law requires them to coordinate with the decision-making body G-BA (Gemeinsamer Bundesausschuss) and Germany’s IQWiG, the Institute for Quality and Efficiency in Health Care. IQWiG examines the advantages and disadvantages of medical services for patients on behalf of G-BA and the Federal Ministry of Health (or on its own initiative).

But how to prove the benefit of a new drug? Since its inception, IQWiG is focusing on evidence-based medicine. Therefore, it will not be enough to demonstrate safety and efficacy. Instead, the focus is on evidence in terms of patient-relevant endpoints, i.e. morbidity, mortality, and quality of life. The law will require the company to provide a wealth of information: does its compound have additional benefits as compared to existing treatment strategies? Is there an alternative for treatment? Which patient (sub)groups will benefit in particular?  Are there special requirements for the treatment? How much will the annual treatment costs amount to? These and many more questions will have to be addressed in the value dossier.

The cost-benefit dossier will then be evaluated by G-BA and/or IQWiG to decide whether the new drug provides additional benefit for patients as compared to existing treatments or not, or whether the new medicine is a “soloist” without any competition.

Pricing

If the assessment comes to the conclusion that there is no proof of additional benefit (or if the company does not submit a value dossier in time), the drug will become subject to Germany’s reference price system. This system sets a price as the interval between the cheapest and the most expensive drug in the particular therapeutic group. If the drug is assessed as providing additional benefit to the patients, the drug maker has to negotiate a rebate on the original price, and this reduced price will be reimbursed after the first year of market introduction. The bill states that negotiations will have to consider international reference prices. There will be a board of arbitration to settle disputes on pricing.

Orphan drugs

As always, the devil is in the details, and procedure and requirements will be outlined only by January 31, 2011. One important point for many biotechs is orphan drugs. The first draft of the bill did not mention them so that they, too, would have been subject to cost-benefit analysis – although they are, by definition, “soloists” as orphan designation is only granted if there is a huge unmet medical need. G-BA stated in an official written comment about the bill dated September 22, 2010, that it opposed any exemptions for orphan drugs. It states that these drugs are granted orphan status solely based on the rareness of a disease, not on missing therapeutic options. “Therefore, approval as ‘orphan drug’ is often granted solely based on surrogate parameters without any reference to patient-relevant benefit,” it states. As examples for orphan drugs without any benefit in terms of patient survival the document mentions Nexavar sorafenib for renal cell carcinoma as well as Volibris ambrisentan, Tracleer bosentan, inhalable Ventavis iloprost, Revatio sildenafil and Thelin sitaxentan for pulmonary hypertension.

In response, BIO Deutschland, the German biotech industry organization  pointed out that orphan drug status in the EU is only granted if, among others, there is “no satisfactory method of diagnosis, prevention or treatment of the condition concerned … authorised, or, if such method exists, the medicinal product will be of significant benefit to those affected by the condition.” BIO Deutschland therefore proposed to except orphan drugs from additional, national benefit appraisals.

The German parliament now decided to except orphan drugs from an additional benefit analysis, provided they do not exceed sales of EUR50 million per year within Germany’s statutory health care system. According to BIO Deutschland, this figure equates to about EUR33 million in net sales.

Impact on clinical trials?

The main question for the design of future clinical trials will be how to demonstrate not only safety and efficacy, but also additional benefit as compared to existing treatments. Evidence-based medicine heavily relies on the evaluation of  long-term patient outcome and comparison studies – but how can a company provide these data at the date of approval? The bill vaguely raises the possibility that G-BA and/or IQWiG may demand additional studies.

The new legislation will also oblige companies to disclose to the authorities the results of all confirmatory clinical trials conducted with the drug, six months after approval at the latest. Publishing can be done in the internet or via linking to a publication, either in German or English language. Publications need to follow GCP-rules and will have to list all results as well as all changes in the study plan, halts, or abortion of trials. In the first draft of the bill it was demanded that companies publish these results.

Consequences

As a result of the new law, companies will have to make sure that they can start marketing their products as soon as they obtain approval in Germany in order to generate high revenue in the first 12 months of commercialization, when they are still free to set the price. After one year, the price will be capped, regardless of whether the drug is assessed as providing additional benefit to patients or not – the only difference is how much the price will be reduced. On a broader scale, the law will not only reduce the prices for innovative drugs in Germany, as Germany today is a reference country for most European states and therefore first-choice market for many biopharmaceutical companies introducing new drugs.