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Off-Label Use in Rare Diseases: Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome and Congenital Myasthenic Syndromes

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Off-Label Use in Rare Diseases: Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome and Congenital Myasthenic Syndromes Review Janzen Rudolf. Off-Label Use in Rare … Neurology Internation- al Open 2018; 00: 00–00 Off-Label Use in Rare Diseases: Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome and Congenital Myasthenic Syndromes Author Rudolf Janzen Institut ABSTraCT former head of department, Neurologische Klinik am The off-label use of licensed drugs is widespread, and the risk Krankenhaus Nordwest, Franfurt Main of adverse events is elevated, especially if the scientific evi- dence is low. The treatment of rare diseases ( < 5/10,000) there- Key words fore may increase the risk of off-label use. The optimized stand- off-label use, refractory myasthenia gravis, Lambert-Eaton ard treatment is primarily based on the regulatory decisions of myasthenic syndrome, congenital myasthenic syndrome the German Federal Joint Committee. The valid guidelines and the regulations of the German health system are discussed in Bibliography this article. The criteria for indication and monitoring of off-la- DOI https://doi.org/10.1055/s-0044-100184 bel use are shown, especially focused on the problem of refrac- Neurology International Open 2018; 2: E118–E123 tory myasthenia gravis. Escalation of treatment results regu- © Georg Thieme Verlag KG Stuttgart · New York larly in off-label use. The arguments within the applicable ISSN 2511-1795 guidelines should be followed. Some new aspects of the Euro- pean regulations are likewise discussed. Correspondence Prof. Dr. med. Rudolf W.C. Janzen Landwehrweg 12 C 61350 Bad Homburg Germany [email protected] Background GKV is available. The extent of the off-label use thus obtained in ac- cordance within the process or outside standard procedure (“toler- Off-Label Use ated” off-label use) has not been systematically investigated in Ger- Off-label use occurs when a licensed drug is applied outside its in- many. With regard to liability, it should be noted that a manufactur- tended use. The intended use of a drug is documented in the official er who is aware of widespread off-label use of a product must be held prescribing information and is based on the related monograph of liable in accordance with Section 84 of the German Drug Law [3]. the German Federal Institute for Drugs and Medical Devices (BfArM) Off-label use is generally associated with an increased risk of ad- [1]. According to a 2017 EU study, the general prescription of a sub- verse drug reactions (ADR), as shown by the recent results of a Ca- stance for off-label use in adults is between 7–95 % in inpatient care, nadian cohort study [7]. According to the study, the average rate and between 6–75 % in the outpatient sector [2]. Numerous guide- of ADRs in general-care on-label use patients was 12.5/10,000 pa- lines of the Association of the Scientific Medical Societies (AWMF) tient months versus 19.1/10,000 patient months in a patient group describe substances used off-label as well as the related level of evi- with off-label use [7]. Such findings, together with the recent EU dence and assessment. Off-label use may be required for the physi- study [2], were the basis for the “Good Off-Label Use Practices” in- cian if these guidelines have clearly formulated the conditions for the itiative of the European Brain Council [8], the core concept of which drug treatment, and the off-label use meets the requirements of the is the promotion of significantly improved pharmacovigilance, sup- various opinions of the Federal Social Court or relevant opinions of ported by the European Myasthenia Gravis Association (EuMGA). the Federal Constitutional Court [3–6] or if no on-label therapy is available for the disease [7]. An assumption of costs by the German Rare diseases: myasthenia gravis statutory health insurance (GKV) can in principle only be made if a Since 2000, diseases with a prevalence of < 5 out of every 10,000 substantiating application is made by the treating neurologist be- people in the EU have been defined as “rare diseases”. According fore the beginning of the therapy as well as a positive opinion of the to a statement by Orphanet regarding myasthenia gravis in Europe health insurance medical service (MDK) and/or prior consent of the [9], this amounts to a prevalence of 1–9/100,000 population. The E118 Janzen Rudolf. Off-Label Use in Rare … Neurology International Open 2018; 2: E118–E123 epidemiological study by Boldingh et al. [10] found a prevalence ably not very attractive to a pharmaceutical manufacturer to un- of between 11.1 and 14.3 per 100,000 for AChR-positive myasthe- dertake classical random clinical trials, e. g., to expand the current nia gravis cases. In Canada, there was a small increase in prevalence authorization. In its “Rapid Report”, the German Institute for Qual- from 16.3/100,000 (1996) to 26.3/100,000 (2013) which is some- ity and Efficiency in Healthcare (IQWiG) indicated that the meth- what related to improved treatment options and diagnostics [11]. odological procedure regarding rare diseases is practically the same On the other hand, new cases of myasthenia gravis between 2.3 as for non-rare diseases [3]. However, even with the concept of and 2.7/100,000 annually seem to be more stable [11]. a rare disease there are “singular cases” [10] or “individual cases”, which are considered “ultra-rare diseases” (prevalence: < 1:10,000), Approved substances and those included by the Joint including, for example MuSK-positive myasthenia gravis (preva- Federal Committee (G-BA) and in the Medicinal lence 0.05–0.65/100,000 [10]) or congenital myasthenic syndrome Products Directive (AM-RL) (CMS) [20]. Consequently, Vrinten et al. [21] introduced the study In German some substances have been approved by the Federal In- concept of a so-called single-case trial, using ephedrine as an ex- stitute for Drugs and Medical Devices (BfArM) for the application ample of add-on therapy for MG. For medicinal products, the con- area myasthenia gravis (▶Fig. 1). These are generally legacy sub- cept of “rare disease (orphan) designation” (formerly: orphan drug stances. However, these were only partially dealt with in the Prepa- designation) was introduced by the EMA for a rare disease and its rations committees (in this case Preparation Committee B3 of the related constellations. The effect of this, for example, was that Federal Health Office), the work of which was discontinued in 1986 3,4-diaminopyridine, which has been known and used for over 40 [12]. In 2004 azathioprine was approved in the post-authorization years and which according to the German New Prescription Formu- procedure for myasthenia gravis. No subsequent approval was re- lary (NRF, no. 22.3) can be prepared by a pharmacy; it can also be quested for ambenonium chloride which was fictively approved in used to treat Lambert-Eaton myasthenic syndrome (LEMS) as a Germany until the end of 1991. Although it is possible to use am- guideline-compliant therapy and has been approved by the EMA as benonium chloride in Germany, an import (according to Drug Law an orphan drug (amifampridine). The high costs of this procedure Section 73 para. 3) from one of the EU member states (France, Po- as well as the procedure itself has been critically discussed [22]. land, Hungary) is required to treat the use as an off-label application. Among the monoclonal antibodies currently in clinical trials, Since the introduction of the “Off-label” expert groups at the eculizumab has received the rare disease (orphan) designation for BfArM in 2006, regulation of some substances by decisions of the myasthenia gravis (EMA: 7/29/2014); this means that the manu- Joint Federal Committee according to Section 35 c, V of the Social facturer has provided proof to the EMA that it provided a “signifi- Security Code could be found [13] for mycophenolate mofetil cant benefit” (Par. 3 of EU directive 141/2000) [23, 24]. In the (MMF, 12/03/2013) and intravenous immunoglobulin G (IVIg, meantime, eculizumab has been approved for the treatment of 9/10/2013). According to AM-RL Annex VI Part A, these may be “therapy-refractory generalized MG with proven antibodies against used for off-label applications without prior request by the attend- acetylcholine receptor protein” (8/14/2017) [25]. Following ap- ing physician. Thus, the basic therapy was extended so that it could proval by the EMA as an orphan drug in Germany, the procedure be described as “optimized standard therapy” (see ▶Fig. 1). The according to the Pharmaceuticals Market Reorganisation Act costs are assumed by the GKV and do not lead to recourse [4]. (AMNOG) for assessing an added benefit is only required if sales of the drug exceed a specified amount (currently EUR 50 million). As Practical application a legacy drug, eculizumab is not subject to an AMNOG procedure. The substances approved in Germany for myasthenia gravis are treated as basic therapy in the current guidelines of the German Function of the neurology/psychiatry expert group at the Neurological Society (DGN) (AWMF registry number: 030/087) federal institute for drugs and medical devices (BfArM) [14]. Not all approved substances are actually used to treat myas- In Germany, regulation of off-label use is following the approach in thenia gravis. accordance with Social Security Code V. The Joint Federal Commit- A Norwegian study [15] analyzed the entire spectrum of pre- tee (G-BA) assign the Off-label Neurology / Psychiatry Expert scribed drugs among 850 patients. Of 527 myasthenia gravis pa- Groups,attached to the BfArM, founded in 2006 to evaluate sub- tients receiving immunosuppressants (IS), the ratio of azathioprine stances used off-label. The assigment requires a request to the Joint to steroids was 32:60 %; a survey in Germany revealed a ratio of Federal Commission (G-BA) made by the German health insurance 77:14 % [16] (see ▶Table 1).
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