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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

Dieter Durand and Susanne Kutter in Wirtschaftswoche feature a disputation between Alzheimer-researcher Konrad Beyreuther and author Cornelia Stolze, who has written a book claiming Alzheimer’s disease does not exist as an exactly defined disease.

While Beyreuther maintains the disease is real and can be clinically separated from other forms of dementia, he concedes that current medications are useless and that diagnosis often is inadequate. Stolze in her book “Vergiss Alzheimer” (“Forget About Alzheimer’s”) states that patients with signs of dementia often are labeled as Alzheimer’s disease patients although they are not, that they receive useless medications, that the real causes of their respective dementias, such as diabetes, depression, stroke, or dehydration, are overlooked and not treated, and that medical doctors make money with unreliable early diagnostic tests. A review of the book is to follow soon – please regularly check the akampioneer.

Joachim Müller-Jung in Frankfurter Allgemeine Zeitung (FAZ) comments on a proposal by several US stem cell researchers in the “Cell Stem Cell” journal. The manifesto calls for establishing a market for human donor egg cells so that scientists can use these cells for cloning experiments. While the purpose is not cloning humans but generating pluripotent human stem cells, Müller-Jung warns that the push will once again put the “cloning humans” debate on the table – a discussion he thinks is needed like a hole in the head. He states there are plenty of experiments already demonstrating that sooner or later it will be possible to generate pluripotent human stem cells for regenerative medicine by reprogramming human body cells.

Martina Lenzen-Schulte, also in FAZ, features the first attempts to use the mirror neuron concept for clinical purposes, e.g. for the rehabilitation of stroke patients to support regain of movement control.

Hildegard Kaulen in FAZ reminds her readers that a substantial part of the research crowned by nobel prizes never received third-party funds. She expresses sympathy with the proposal put forward in “Nature” by Stanford University’s John Ioannidis to either allocate research grants by lottery, by dividing up the money so that each applicant receives the same amount, or simply by handing out money to outstanding scientists with the only specification to use it for research. He criticizes that it has never been investigated which method to allocate research grants is the best and that the current practice consumes too much valuable time that should be spent more creatively on research.

Die Welt reports in a feature by dpa on material scientists of the Technical University Dresden who use wood for pipes that are as strong and resilient as pipes made from concrete. Wood is cut to rectangular blocks, which are heated to 140°C and compressed. Subsequently, all air – which amounts to up to two third of the wood’s volume –  is removed. The resulting panels are then bonded and formed by applying steam. The team led by Peer Haller of the university’s Institute for Steel and Wood Construction calculates that a post carrying 50 tons of weight needs 155 kg of steel but only 28 kg of wood treated with the new procedure.

Katrin Blawat in Süddeutsche Zeitung (SZ) reports that Umckaloabo, an alcoholic extract of Pelargonium sidoides roots, is under investigation by Germany’s Federal Institute for Drugs and Medical Devices (BfArM). The medication, which is sold as OTC in Germany for the treatment of acute bronchitis (with annual sales of about € 40 million), is suspected to cause inflammation of the liver, with six cases reported in 2011.

The New York Times (NYT) this week deals in-depth with the recommendation of the United States Preventive Services Task Force that men no longer should have an annual prostate-specific antigen (PSA) test. Gardiner Harris interviewed the experts involved in reviewing PSA testing, citing Dr. Roger Chou, an associate professor of medicine at the University of Oregon, as saying “the idea that knowing you have a cancer isn’t always a good thing is a very difficult concept for many people.” Chou states that the vast majority of men who have prostate cancer will never be bothered by it. Urologists however view the issue differently, stating the task force chose to focus on the wrong studies and it was wrong to throw PSA testing away.

Last not least, in preparation of the coming common cold season, Ulrike Gebhard in Neue Zürcher Zeitung (NZZ) explains that men suffer from the common cold more often than women. Reason is – according to researchers from Belgian Gent University – that women often carry extra portions of genes from the toll-like receptor (TLR) gene family. As a result, they produce more of the so-called miRNA molecules that support the body in fending off viral infections. The downside of women’s more powerful immune system is increased susceptibility to autoimmune diseases and a more violent reaction to certain vaccines.

Food for Thought: How Can Biotech & Medtech Companies Benefit from SEO?

There are a lot of service providers offering Search Engine Optimization (SEO). But what do biotech and medtech companies really need to increase their online visibility? Three things are essential in our view:

First, if someone has heard about your enterprise, he or she should find your company’s name and website among the top three entries of Google’s search engine hit list. Ideally this should also work if the user spells the name wrong.

Second, a user should find your company by typing in a short string of keywords. As an example, an investor, journalist etc. might be interested in looking for biotech companies developing novel antibodies for the treatment of baldness. In this case your company should show up on the first page of Google hits if the user has typed in “biotech” “antibodies” and “baldness” or “novel treatments” and ”baldness”.

Third, your company should show also up in search results covering a broader field. In the example given above, a search engine should retrieve your company’s name and website for “biotech” and “antibodies” and rank them as high as possible.

The rest of SEO is negligible for biotech and medtech companies as they are not selling consumer goods. Did you ever meet a potential collaboration partner who has screened thousands of Google hits related to your company? Probably not. If you are lucky, he may have read about your company in one of the important trade publications and already has you on his radar. If you are not so lucky, he may wonder why he has never read anything about your company in one of those important trade publications – despite your leading-edge technology and thousands of Google hits.

But how to accomplish the three goals mentioned above? There are no tricks involved – feel free to spend a lot of time and money trying to outsmart Google’s algorithms but you will learn that Google adapts faster than a bacterium acquires resistance to penicillin.

SEO success is based on carefully crafted key messages on your company, a bit of HTML editing and constant work to keep your website up-to-date, presenting new and interesting and – above all – relevant content.

The main task is to carefully think about the keywords important for your business. These need to be presented on your website in a way that Google’s earch engine can see and recognize them. This requires basic knowledge of HTML – not a lot more. The most important task is continuous communication – keep the world updated by adding news and novel information and by providing useful links, e.g. to pharma and academic partners, articles, patents, wikipedia entries relevant for your business, official statistics, market data, etc.

Thereby, you will not only ensure that your company shows up in search engine results prominently, but you will also build your company´s reputation among people interested in your field.

If you want to know more, please do not hesitate to contact us.

 

Food for Thought: Weekly Wrap-Up

Volker Stollorz in Frankfurter Allgemein Sonntagszeitung (FAS) this week in detail reports on a paper describing the generation of pluripotent stem cells from adult human testis, which has raised suspicions because as yet no one has been able to reproduce the data or cell lines. The paper published 2008 in Nature raised high hopes about the generation of pluripotent human stem cells for research and therapy without technically or ethically debatable interventions. The research originated in the lab of Thomas Skutella, then at the University of Tuebingen, Germany; lead author was Sabine Conrad. Already, researcher Hans R. Schoeler in the same journal expressed concerns that the cells used by Conrad et al. are not pluripotent as described. The article by Stollorz is not yet available online.

Stephan Sahm in Frankfurter Allgemeine Zeitung (FAZ) introduces the new medical discipline of neurogastroenterology which deals with the nerve cells lining the human digestive tract. Already it is known that impairments of these nerve cells lead to motility disturbances of the colon – often seen in diabetics – and to dysfunctions of the immune system.

In the same paper, Hildegard Kaulen describes attempts to understand and cure chronic fatigue in cancer patients. The syndrome often appears after successful tumor eradication by chemo- or radiation therapy and has been neglected by clinicians and doctors in the past.

In Die Welt, Joerg Zittlau introduces a new silicon-based coating developed by Nanopool GmbH. The liquid glass coating is non-toxic, heat- and scratch-resistant and extremely thin and flexible. It is made by extracting nano-sized silica crystals from sand which are subsequently mixed with water and alcohol and applied either manually or by spraying. Once the solvent has evaporated, the glass coating is ready. As it is extremely smooth it is not only suited as protectant but also stain-resistant and self cleaning.

Wolfgang S. Merkel, also in Die Welt, explains why certain materials such as asbestos or nanotubes are dangerous for cells. If particles have a rounded tip they are mistaken by the cells for a small spheric particle and taken up. As the process cannot be terminated for the length of the particle, the cell eventually dies and, if many cells are affected, inflammation and cancer may arise.

Christina Berndt in Sueddeutsche Zeitung (SZ) deals with the latest conspiracy theory spread by ecological fundamentalists: milk is dangerous for toddlers as it blocks the mucosa with phlegm so that it cannot ward off infections. In the same paper, Berndt reports on fundamentalist Taliban in Pakistan opposing vaccination. As a result, polio cases have risen dramatically in the areas controlled by the Taliban.

Hartmut Wewetzer in Der Tagesspiegel introduces latest findings demonstrating that neither resveratrol, the highly acclaimed ingredient of grapes, nor sirtuin proteins guarantee longer, healthier life. Previously, researchers from the US had claimed that sirtuin proteins, which are activated by resveratrol, mediate longer life. In contrast, Nicholas Wade in The New York Times reports on the same study and points out that there is a trans-atlantic rift in reporting: while British scientists say sirtuins are not involved in longevity, the US colleagues under attack say they adhere to their claim. The controversy is around the genetic uniformity or diversity of the animal strains used in the experiments.

Larry Husten in Forbes is commenting on the decline of cardiovascular procedures observed in US hospitals, speculating that four factors may contribute to it: concerns about stent overuse, the payoff of preventive drug treatments, the larger economic climate and recent investigations into implantable cardioverter defibrillator (ICD) by the US Department of Justice. Recently, doctors and hospitals in the US were accused to implant ICDs without proper evidence base in more than 1 in 5 cases.

Also in ForbesDavid Shaywitz and Dennis Ausiello in a commentary demand that doctors translate research results into clinical progress much better than today. The authors do not focus on the “translational science” buzzword but propose simple things: improvements in measurements, a less intrusive medicine and better participation of patients, e.g. by involving Facebook- or smartphone-based information transfer for better compliance and health status surveillance.

In the New Scientist, Debora MacKenzie reports on Sanofi-Pasteur signing a contract with the University of San Diego, Calif. to develop a vaccine for the prevention and treatment of acne, a disease affecting 85% of teens. The challenge: killing the disease-causing bacterium (which is benign under normal circumstances and turns nasty only in clogged sebaceous glands in the skin) is likely to disturb the important, delicate balance of the skin’s normal bacterial community. The solution may be to use an antibody directed specifically against a protein released by the acne-causing bacteria, if  oxygen levels fall below normal in the clogged glands. This approach may neutralize the acne factors and prevent inflammation while leaving the normal bacterial community on the skin undisturbed.

Last not least, physics nerds make a laughing matter of CERN’s latest discovery that neutrinos may travel faster than light, reports Holger Dambeck in Der Spiegel. Our favorite one (true Monty Python style) is as follows: “To reach the other side. Why do neutrinos cross the road?”

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