Generic substitution in epilepsy - influence and effects of discount contracts

The aim of the drug discount agreements in accordance with Section 130a Paragraph 8 of the Social Code V (SGB V) is to promote the exchange of drugs with the same active ingredients in accordance with Section 129 SGB V and thus reduce the drug costs of statutory health insurance companies. Due to the sharpening of discount agreements by the GKV-WSG on April 1, 2007, the topic of drug substitution has increasingly become the focus of interest and health policy discussions. However, replacing a medication with a discounted product is not always without risks. There are certain diseases or “critical indications” for which substitution is problematic due to the discount agreements agreed between drug manufacturers and statutory health insurance companies. This particularly affects patients with long-term drug therapy, such as: E.g. epilepsy patients or so-called “critical dose drugs” (active ingredients with a narrow therapeutic range). Exchanging drugs can have negative effects on the further course of the disease (seizure recurrences, toxicity), at least in well-controlled patients with epilepsy. The German Society for Neurology (DGN) therefore warns in its guidelines against an uncontrolled exchange of antiepileptic drugs in stable and well-controlled patients (DGN 2008).

>> After the modified framework agreement came into force in April 2008, in which the substitution obligation in discount agreements was clarified with regard to the same or interchangeable dosage forms to the extent that the same dosage forms now also became interchangeable for which the Federal Joint Committee had not previously defined any interchangeable groups As expected, there will also be an increase in generic product switching among epilepsy patients. In addition, there is the assumption that the number of patients with a switchback (switching to the already known original product after a generic product change has already taken place) is comparatively high in the case of antiepileptic drugs. A study from Canada published in 2007 already provided evidence of this (Fig. 1). A working group at McGill University in Montréal examined the frequency of switchback rates to the already known original product in epilepsy patients after generic substitution and compared these with the switchback rates of patients receiving treatment with a lipid-lowering drug or an antidepressant. It was shown that the switchback rates in the patient group treated with antiepileptic drugs were significantly higher with both monotherapy and combination therapy than in the two comparison groups (Andermann et al. 2007).
This raises the question of what the situation is with regard to generic substitution in epilepsy before and after the introduction of the discount agreements and the modified framework agreement in Germany.
The Hamburg pharmaceutical company Desitin Arzneimittel GmbH recently approached the Deutsches Arzneiprüfungsinstitut e.V. association with this question using the example of valproate therapy. V. (DAPI). Medicines containing valproate/valproic acid are available on the market as juice, drops, solution for injection and oral solid dosage form. These finished medicinal products are available as a sodium salt (e.g. Ergenyl® or Orfiril®), as a free acid (e.g. Convulex®) or as a mixture of valproic acid and the corresponding sodium salt (e.g. Ergenyl® chrono). The DAPI has a comprehensive database available, which consists of anonymized prescription data for medicines that were dispensed in public pharmacies in Germany at the expense of the statutory health insurance companies (GKV) (DAPI 2009). Since this question also seemed interesting to the DAPI and worth investigating, a joint study project was subsequently launched, which was intended, on the one hand, to answer the question of whether there was a need for substitution by discount agreements and their "sharpening" before and after the entry into force of the "compulsory obligation". “ as a result of the adjustment to the framework agreement
Product changes and differences in the frequencies or incidence rates of product changes between the individual valproate product groups occurred (Schüssel et al. 2010). On the other hand, the question should be investigated whether before and after the substitution obligation came into force through the discount agreements and their “readjustment” there was an increase in switchback rates in patients taking valproate therapy as a result of a generic product change.
Objective
The basis of the study project by the company Desitin and DAPI was the assumption that there was an increase in generic product changes and switchback rates among epilepsy patients after the modified framework agreement came into force in April 2008. The aim was, based on case-related data, to present a comprehensive analysis of the effects of the aforementioned health policy regulations on the care situation for epilepsy patients using valproate therapy as an example.
In the first phase of the study project, the frequency and incidence rates of a generic product switch in epilepsy were to be examined using the example of therapy with valproate. Taking into account the entry into force of the discount agreements and the change in the framework agreement from April 2008, the incidence rates of generic product switching in the years 2006, 2007, 2008 and 2009 were to be evaluated, with a distinction being made between treatment groups of epilepsy patients who either did not use sustained-release valproate products (NRET), retarded valproate products (RET) or the antiepileptic drug Orfril® long, which is also retarded. The group with the Orfril® long products from Desitin Arzneimittel GmbH was defined as a separate study arm because these sustained-release formulations are so-called “multiple units of pellets”. These mini tablets have a diameter of a few millimeters and - in contrast to conventional extended-release tablets - can be taken independently of meals.
Among other things, stratification should also be made according to the type of antiepileptic therapy (monotherapy or combination therapy) and the duration of previous treatment with valproate.
In the second phase, the aim was to examine the frequency or incidence rates of switchbacks in patients receiving valproate therapy with a generic product switch, ie a switch to the already known original product. A distinction should be made again according to the years 2006, 2007, 2008 and 2009 as well as the product groups NRET, RET and Orfril® long. Furthermore, it was of interest, among other things, whether there are differences between the different types of antiepileptic drug therapy (monotherapy or combination therapy) with regard to the frequency or incidence rates of switchbacks in patients treated with valproate after a generic product switch.
methodology
In the data available from DAPI, the proportion of patients treated with valproate who had a product switch between 2006 and 2009 was first determined and the incidence rates were calculated. A distinction was made between therapy groups that received a non-retarded or a sustained-release valproate product or Orfril® long as the original drug. The aim of carrying out the evaluation of the data separately for the years 2006, 2007, 2008 and 2009 was to be able to better represent the influence of the sharpening of the discount agreements in April 2007 and the changes to the framework agreement in April 2008. For this purpose, all valproate prescriptions were initially identified as so-called index prescriptions in the index periods from 2006 to 2009. An index prescription was the last valproate prescription in the first quarter of a year. Subsequently, depending on the respective product group (NRET, RET, Orfril® long), the number of patients with valproate prescriptions in the treatment years 2006 to 2009 as well as the number of patients who received at least one further follow-up prescription for valproate within 120 days of the index prescription were determined -containing preparations were identified.
In order to be able to obtain data about a product change that had taken place, the subgroup of patients per year of treatment was determined who had received a different product than the index prescription as a subsequent prescription. This in turn was carried out stratified according to the following criteria: valproate product group (NRET, RET, Orfril® long), the type of antiepileptic therapy (mono- or combination therapy) and the duration of valproate pretreatment. Patients with a product switch were then identified in whom a switchback to the original product of the index prescription occurred within 180 days of the switch.
In the last step, for each individual treatment year (2006, 2007, 2008 and 2009), separately according to the respective product groups (NRET, RET, Orfril® long) and taking into account the different types of antiepileptic therapy (mono- or combination therapy), the Proportion of patients and incidence rates with switchback as well as the Kaplan-Meier estimates at the end of 180 days. With the help of the Kaplan-Meier estimator, the probability can be estimated that a specific event will not occur within a time interval for the person being examined - in this case, no switchback has occurred.
Patients who had another product change in the observation period after the subsequent prescription were not included. Patients who switched to a galenic form that deviated from the index prescription or the subsequent prescription were also excluded. A galenic change is, for example, the change from a sustained-release drug form to an unretarded one.
Results
The study group included 575,531 index prescriptions between 2006 and 2009. The number of patients, however, was 320,690 people. This can be explained by the fact that patients are often treated for many years and some of them are included in different years with index prescriptions. Based on the total of 575,531 index prescriptions in the treatment years 2006 to 2009, it was determined that 368,824 follow-up valproate prescriptions were made within a period of 120 days from the index date. The final study population here ultimately comprised - again after excluding certain follow-up prescriptions that did not meet the study design - 353,078 follow-up prescriptions or 180,573 patients. On the basis of this study group, 40,400 medication profiles with product changes were finally identified in the four different treatment years and the individual product groups.
The evaluation of the data itself showed that the frequency or incidence rates of a generic product switch were consistently low only in the Orfril® long treatment group over the four years of treatment from 2006 to 2009 and even tended to decrease slightly overall. In 2008, after the modified framework agreement came into force, there was a significant increase in the rate of product switching in the NRET and RET groups - but not in the Orfril® long treatment group. In 2009, the rate of product changes fell significantly again compared to the previous year, particularly in the NRET group (Fig. 2).
The incidence rates of product switching in patients receiving combination therapy with valproate and other antiepileptic drugs were higher than the product switching rates in patients receiving valproate monotherapy only in the RET and Orfril® long treatment groups. No such observations could be made in patients treated with other non-sustained-release anti-epileptic drugs (NRET). It was shown that patients with the index prescription Orfril® long or extended-release valproate product (RET) in the case of combination therapy had a slightly higher incidence rate of product changes than patients who received valproate in monotherapy.
With regard to the criterion “duration of valproate pretreatment”, it was found that in patients without valproate pretreatment in the year before the index prescription, the overall incidence rates for product switching were lower than those for people who had undergone valproate treatment in the first or in the first and second periods. had already received valproic acid the year before the index prescription. It could be concluded that physicians may want to avoid switching products in patients without prior valproate treatment during the adjustment and dose determination phase.
The switchback rates determined in the patient cohort with product switching using the Kaplan-Meier method were comparatively high in all 3 treatment groups over the observation years 2006 to 2009 (between 29.7 % and 48.2 %). In addition, it could be seen that the switchback rates, which were determined using the Kaplan-Meier estimator, increased significantly in 2007 compared to 2006. In 2008 and 2009, a further increase in switchbacks was observed in the Orfiril-long group, whereas they decreased slightly again in the RET group. The incidence rates for a switchback in the group of patients who were treated with other non-sustained antiepileptic drugs even fell significantly in 2008 - to below the level in 2006.
The incidence rates of switchbacks in patients who had received other prescriptions for antiepileptic drugs other than valproate within 180 days before the index date (combination therapy) were greater than in patients with valproate monotherapy in all years of treatment. This could be an indication that patients who required broad drug therapy returned to their familiar original product more often after a product change.
Conclusion
The generic exchange of medications in epilepsy has become more important with the entry into force of the discount agreements and the modified framework agreement according to Section 129 SGB V in 2008. In the present analysis of data from the Association of German Medicines Testing Institute e. V. (DAPI), using the example of valproate therapy, was able to show that although generic substitution for epilepsy patients was already common in Germany in 2006, it increased significantly after the discount agreements were “sharpened”. However, this did not apply equally to all valproate treatment groups. Product switching in 2008 was particularly pronounced in patients who were treated with prolonged-release antiepileptic drugs (RET) other than Orfril® long or with non-sustained-release products (NRET), with the incidence rates for product switching tending to be slightly higher in the RET treatment group than in the NRET group. An exception was the antiepileptic drug Orfril® long, sold by the Hamburg CNS specialist Desitin. Orfril® long showed the lowest overall generic switching rates over the treatment years examined from 2006 to 2009 and was almost affected in this regard by the sharpening of the discount agreements and the entry into force of the modified framework agreement unaffected. This suggests that patients who have been started on Orfril® long have a comparatively high level of product adherence. A possible reason for this could be, among other things, the dosage form (sustained-release mini-tablets).
In the selected group of patients with a product switch, switchbacks to the already known valproate original product occurred frequently in the treatment years 2006 to 2009, increased significantly in 2007 compared to the previous year in all treatment groups (NRET, RET and Orfril® long), then were However, in the following years, with the exception of the Orfril® long treatment group, it partially declined again.
The present results of the study project on the influence and effects of discount contracts in epilepsy using valproate therapy as an example may be an indication that product changes and switchback rates among epilepsy patients in Germany are comparatively high.
International studies from Canada from 2007 and 2008 also showed that the switchback rates for antiepileptic drugs were significantly higher than those for statins and SSRIs (serotonin reuptake inhibitors) or statins and antihypertensives (Andermann et al. 2007 ; LeLorier et al. 2008).
When interpreting the study results, it should be critically noted that the different discount contract models of the cost bearers can lead to different substitution rates and the associated product switching rates. The regionally inhomogeneous aut-idem behavior of the doctors was also not taken into account. Another parameter that could potentially influence the product change is the sometimes inconsistent implementation of the discount contract-related substitution obligation in the pharmacies' software systems.
outlook
For patients with epilepsy, maintaining seizure freedom is critically important both medically and socially. In the case of epilepsy, even a single recurrence of the disease in the form of a seizure can have far-reaching socio-medical consequences. In addition to a possible loss of driving license, as well as loss of school or work or job loss, the psychosocial aspects can also be of great importance.
The current high sensitivity of the substitution problem in epilepsy therapy can also be seen in current statements from various opinion leaders in the health policy landscape and medical stakeholders. This is how e.g. For example, the North Rhine Association of Statutory Health Insurance Physicians (KV) in Düsseldorf recently discussed the problem of generic substitution for “critical dose drugs” in its magazine “KVNO aktuell”, such as: B. antiepileptic drugs, and recommends not switching patients who are stable on “critical dose drugs” (KVNO aktuell 2011).
The Federal Association of the Pharmaceutical Industry also e. V. (BPI) takes a position on the topic in a position paper from May 2011. It is also pointed out here that in the case of “critical indications”, such as epilepsy, or medications with a narrow therapeutic range (critical dose drugs), such as antiepileptics, there is a risk of a worsening of the seizure situation in the event of a generic product change. Since patients are not legally protected against exchange, the BPI experts suggest creating a “critical dose drug list”. This should contain indications and active ingredients for which replacement in the pharmacy is prohibited and the prescription is not checked for “cost-effectiveness” (BPI 2011). The results of the study project presented show, analogous to the opinions of the experts, that there is an urgent need for action with regard to the existing substitution obligations for the critical indication of epilepsy. <<