Statement on the “Interchangeability of drugs with a complex active substance composition”
The non-biological complex drugs (NBCD) consist of four drug groups: the low-molecular-weight heparins, the glatiramoids, the iron carbohydrate complexes and the liposomal parenterals (e.g. containing the active substance doxorubicin). They all share the common feature of being drugs with a complex composition. As they also include the low-molecular-weight heparins, however, which are biological in origin, the term “non-biological complex drug” is a legitimate subject for debate. None of the products is of biotechnological origin (i.e. a biological), however, which is to be conveyed by the internationally introduced name “NBCD”.
In principle, all NBCDs differ very significantly from drugs with small, chemically defined molecules, in that:
- they consist of a range of very similar complex components rather than having a unified molecular structure,
- the total mixture of similar molecules is to be considered as “the active substance”,
- it has not yet been possible to characterize the complex features by means of physico-chemical analyses,
- a consistent, carefully monitored manufacturing process is essential for ensuring the product’s uniformity and reproducibility and
- the clinical significance of any differences in the complex product features, such as immunogenicity, is largely not or only partially understood.
This very complex molecular and/or product structure makes it practically impossible to develop generic alternatives, i.e. products with an identical molecular composition. Instead, with these drugs, each product’s composition is determined by its special manufacturing process (“the process is the product”). To this extent, distinguishing this group from those drugs with a chemically defined composition is not only meaningful but also essential.
Apart from the complexity of their composition, the various NBCD drugs have no immediate similarities. To date, therefore, there has been no uniform regulatory concept for them. The low-molecular-weight heparins do constitute a special case, however, because their biological origin means that, in Europe, they are treated as biosimilars for regulatory purposes.
Due to their non-biological origin, the glatiramoids, iron carbohydrate complexes and liposomal parenterals cannot be correspondingly classified, despite the fact that their complex composition also precludes any generic development. Even using the most efficient, highly sensitive and selective analytical methods currently available, the products’ molecular composition can only be insufficiently characterized. Of course, this applies in equal measure when comparing originator drugs with imitator (me-too) products, for which it is thus not possible to provide unequivocal confirmation of an identical composition. Such products can therefore only be classified as “similar”. As a result, in contrast to the generics, an authorization that references another product based on proof of bioequivalence is definitely not acceptable in such cases. Instead, there must be a requirement for comprehensive pharmaceutical/analytical investigations and preclinical and clinical trials, equivalent to those seen during the development of biosimilars, comparing the originator drug in each case.
This fundamental appraisal applies not only to the preconditions for authorization in the European Union but also to the assessment of the “interchangeability” of the NBCD in the course of its therapeutic application. This aspect has been clearly regulated for biosimilars, as an aut-idem substitution is excluded in principle pursuant to section 129 subsection 2 of the German Social Security Code, Book V. This decision is substantiated by the complexity of the product composition, which ensures only “similar”, but possibly not really identical, clinical efficacy (and safety). In addition, the clinical comparative studies are not generally designed to encompass a switch from one product to another during an ongoing treatment. This rule should be extended to the other NBCDs, which are to be similarly assessed in this regard.
Detailed analysis of specific NBCD features leads to the conclusion that, in view of their particular product features with their very complex composition in all cases, a simple authorization referencing another product, solely supported by evidence of pharmacokinetic bioequivalence based on a single ingredient, is definitely not acceptable. To ensure safety of treatment in such cases, clinical studies confirming efficacy and safety are essential and should always be performed in comparison to the originator drug (if necessary, supported by comprehensive pharmacodynamic investigations). In each case, it must be ensured that the comparable therapeutic effects for the me-too products can be confirmed with the aid of adequate clinical or paraclinical (e.g. medical imaging procedures) endpoints. It remains to be seen to what extent this will actually occur for the products in question. From the point of view of medical professionals, who ultimately have to deal with this problem in practice, it should also be ensured that the evidence obtained from these clinical studies is provided in a form that allows them to fulfil their responsibility of always providing their patients with an effective and safe drug therapy. In addition, it is important that the safety of me-too products continues to be observed and monitored during their therapeutic use in the form of post-authorization safety studies.
For those NBCDs used in the long-term therapy of a patient whose drug dosage has been carefully titrated, an aut-idem substitution can therefore – analogous to the biosimilars – not be recommended until confirmation of “therapeutic interchangeability” is available. Based on current scientific evidence, the German Pharmaceutical Association (Deutsche Pharmazeutische Gesellschaft [DPhG]) considers it advisable to include the NBCDs on the “List of medicinal products excluded from substitution” published by the Federal Joint Committee (Gemeinsamer Bundesausschuss), provided that, as biosimilars, they are not already excluded from substitution, as is the case with the low-molecular-weight heparins.
This statement was prepared on the basis of the results of a consultation of experts organized by the German Pharmaceutical Association [DPhG]) together with the House of Pharma & Healthcare, Frankfurt. The following members of the expert panel contributed to the preparation of the statement and support the recommendations formulated therein:
|Prof. Dr. Susanne Alban, Kiel||Prof. Dr. Stefan Laufer, Tübingen|
|Dr. Michael Binger, Wiesbaden||Dr. Martin Lorenz, Frankfurt|
|Prof. Dr. Henning Blume, Oberursel||Prof. Dr. Jochen Maas, Frankfurt|
|Prof. Dr. Wolfgang Brück, Göttingen||Dr. Milan Novakovic, Berlin|
|Dr. Joachim Burschäpers, Frankfurt||Prof. Dr. Friedemann Paul, Berlin|
|Prof. Dr. Theodor Dingermann, Frankfurt||Dr. Otto-Quintus Russe, Frankfurt|
|Dr. Daniel Fendji, Berlin||Prof. Dr. Manfred Schubert-Zsilavecz, Frankfurt|
|Prof. Dr. Sebastian Harder, Frankfurt||Prof. Dr. Fritz Sörgel, Heroldsberg|
|Prof. Dr. Eva Herrmann, Frankfurt||Dr. Gerhard Tischler, Berlin|
|Lothar Jungbluth, Obertreis||Dr. Christian Ude, Darmstadt|
|Prof. Dr. Michael Lämmerhofer, Tübingen||Dr. Dagmar Walluf-Blume, Berlin|