Tag: Federal Joint Committee

Food for Thought: Greek Ghosts Haunting Pharma

Up to the end of 2010, pharma companies were able to set the price for innovative new medicine at will upon introduction to the German market. Under the new AMNOG law, however, the price is dependent on the degree of innovation, as assessed by G-BA (Federal Joint Committee). G-BA requires pharma and biotech companies to provide information on medical benefits and advantages as compared to existing medicines across all indications the drug is approved for, and statistics on the (sub)sets of patients who will benefit from the drug. In addition, they have to provide spending figures of the statutory healthcare system and need to explain how quality can be assured during treatment.

G-BA can mandate the Institute for Quality and Efficiency in Healthcare (IQWiG) with the assessment (to make matters more complex, IQWiG can assess drugs and treatments also without assignment by G-BA) and once it has come to a conclusion, it needs to call for opinions of all parties (manufacturers, reviewers/experts, head organizations of patient/self-help groups and medical associations, etc.) – written statements as well as hearings.

If at the end of the process G-BA comes to the conclusion that the respective drug does not provide additional benefit, the medicine is subject to reimbursement under Germany’s fixed-price system and will be reimbursed in the price range of drugs already marketed in the same indication(s).

However, if the new medicine is ruled innovative, the bazaar is open: lobby groups of the pharmaceutical industry, including generics manufacturers, start debating with G-BA and representatives of the statutory healthcare system. The interesting part of this procedure is that pharma companies have to provide data on the selling price in “other European countries”.

But which are these “other” countries? With the European debt crisis, the debate has become heated: while manufacturers demand to select countries with similar economic power as comparators (such as France or UK), the statutory healthcare insurers are advocates of including Europe’s weakest economies: Greece, Portugal, The Czech Republic, Slovakia, etc. To resolve the problem, an arbitration board was founded.

Since last week, the jury is out, and it is not in favor of manufacturers. The arbitration board selected 15 European countries as reference countries for price fixing. The list comprises Austria, Belgium, the Czech Republic, Denmark, Finland, France, Greece, Ireland, Italy, The Netherlands, Portugal, Sweden, Slovakia, Spain, and the UK. At least five of them are economically weak countries with low drug prices.

The ruling will have consequences not only for Germany. If, as a result, prices for innovative medicines in Germany come down, prices elsewhere in Europe might follow as Germany is a reference country for pricing in many other European countries. To avoid a downward spiral, manufacturers may choose to introduce novel innovative drugs in Germany only with a considerable delay.

Food for Thought: It’s becoming a habit – IQWiG takes approval studies apart

Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) this year put out several negative assessments of newly introduced drugs, stating the data did not prove “additional benefit” over existing treatments. In all cases, IQWiG came to the conclusion after deviating from the study design the companies had discussed with the regulators. Instead, IQWiG’s experts divided the patient population into subgroups, saying those subgroups needed different comparator treatments. As a result, these data were either not available or the subgroups were too small to demonstrate statistical significance.

One example is Pfizer’s Xiapex injectable collagenase, approved in early 2011 to treat Dupuytren’s contracture. IQWiG stated that Xiapex does not provide an additional benefit to patients because “it was not possible to derive such additional benefit from the dossier and because the manufacturer did not provide additional or suitable data” to substantiate the claim.

While the manufacturer had compared the Xiapex injection to a surgical treatment, partial fasciectomy (PF), IQWiG for its assessment established six subgroups of patients according to the severity of the disease and chose three different treatment options as comparator: no therapy, percutaneous needle fasciectomy (PNF) and partial fasciectomy (PF). As a result, IQWiG was able to state that Pfizer did not provide evaluable data because the company’s selected comparators differed from IQWiG’s comparators for all but one patient subgroup.

In the case of Eisai’s breast cancer drug Halaven eribulin, IQWiG’s verdict ruled that it could not find evidence for eribulin resulting in a prolonged life expectancy. IQWiG added that Halaven might provide an overall survival benefit for patients for whom taxanes or anthracyclines are no longer an option, but it was unclear whether the benefit was significant. Again, the assessment was made by subdividing the patient group. IQWig defined two subpopulations – one for which an additional anthracycline or taxane treatment was thought to be an option and one for which this was not.

Eisai, in contrast, had compared Halaven to a “Treatment of Physician’s Choice” (TPC) as there are no established national or international treatment guidelines for a standard therapy of women with metastatic or locally advanced breast cancer after failure of two standard chemotherapies including an anthracycline or taxane. This design of Eisai’s EMBRACE was established in discussions with the European Medicine’s Agency (EMA). Being a European study, the participating physicians sometimes opted for therapies not approved in Germany – a reason for IQWiG to not include these data in its assessment. As a result, only 69% of the EMBRACE study patients were regarded as suitable for an assessment.

The same approach was taken in the assessment of Novartis’ Gilenya fingolimod, the first oral treatment for Multiple Sclerosis (MS) approved in 2011. IQWiG once again performed separate assessments of the drug in three groups of patients, choosing three different comparators. Following this operation, IQWiG was able to find data only for one of these subgroups in the study, not enough to establish an additional benefit with sufficient statistical significance. However, one of the comparisons chosen by IQWiG – fingolimod against glatiramer acetate in patients with relapsing/remitting MS – would have been impossible as fingolimod is approved as second-line therapy in this indication while there are no studies of glatiramer acetate differentiating between first-line and second-line treatments.

In all cases, manufacturers may respond to the assessment, after which the Federal Joint Committee (G-BA) will review IQWiG’s recommendation before making a final decision.  If G-BA deviates from IQWiG’s negative assessment, the manufacturers have to negotiate the price with the Statutory Health Insurance Funds Association (GKV-Spitzenverband) under the AMNOG pricing scheme. If G-BA agrees with the IQWiG assessment that a drug has no clinical benefit beyond available treatments, the drug will be added to the reference pricing system, which gives the same base price to all comparable drugs in the respective therapeutic group.

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.”