Swiss Biosimilars Update Embraces Foreign Comparators
Executive Summary
Switzerland’s regulatory agency is open to accepting foreign comparator products for biosimilar applications. But bridging studies are likely to be required, its latest guideline suggests.
Using a foreign comparator product in biosimilar applications, rather than referring to the Swiss-authorized reference product, is appropriate, Switzerland’s medicines agency, Swissmedic, has clarified in an update to its overarching biosimilar guideline. The revised guidance document, in force from 29 May, also now explicitly includes low molecular weight heparins (LMWHs) such as enoxaparin within the scope of its regulatory framework for biosimilars.
Section 5.4.1 of the guideline, discussing the comprehensive comparability exercise, recommends using a single comparator product. “This should preferably be the reference product from Switzerland,” it states, “although a similar product from the European Union or the US market is also acceptable.” Comparator products from European Free Trade Association (EFTA) member countries such as Norway, Iceland and Liechtenstein will also be accepted, provided they are also authorized in the EU.
Where biosimilar applicants chose to use a foreign comparator, even though a reference drug is already authorized in Switzerland, the agency says it will make two demands.
“If additional comparator products from the EU or US market are used for clinical efficacy trials, a three-way bridging between the biosimilar, the EU and the US comparator products should be submitted” – Swissmedic
Firstly, the international non-proprietary or active substance name, pharmaceutical form, dosage strength, qualitative composition and route of administration must be identical to that of the Swiss reference product.
Need To Compare With Corresponding Clinical Trials
Secondly, for all the reference brand’s indications authorized in Switzerland, the applicant will have to present a comparison with the corresponding clinical trials for the chosen comparator product.
“If additional comparator products from the EU or US market are used for clinical efficacy trials,” Section 5.4.1 states, “a three-way bridging between the biosimilar, the EU and the US comparator products should be submitted. This requirement, it points out, is line with EU’s overarching biosimilars guideline CHMP437/04 Rev 1, which says that “if certain clinical and in vivo non-clinical studies of the development programme are performed with the non-European Economic Area authorised comparator, the applicant should provide adequate data or information to scientifically justify the relevance of these comparative data and establish an acceptable bridge to the EEA-authorised reference product.”
On a case-by-case basis, Swissmedic plans to determine whether clinical pharmacokinetic and/or pharmacodynamic data for all three products are required. In general, it adds, applicants should be able to justify the suitability of additional comparator products, noting that specific questions can be addressed during a scientific-advise or pre-submission meeting.
Three-way bridging is also required if applicants seek to use products from acceptable third countries for supplementary clinical or in vivo pre-clinical studies. As countries with “comparable medicinal product control”, Swissmedic currently recognizes EU and EFTA member states and the US, as well as Australia, Canada, Japan, New Zealand and Singapore.
Porcine Mucosa Is Seen As Starting Material
LMWHs are now explicitly mentioned in Swissmedic’s guideline as falling under the framework for biological medicines. In Section 7.4 covering Module 3 on documenting analytical, chemical and pharmaceutical tests, the agency states: “In the case of heparins, including LMWHs, the porcine intestinal mucosa constitutes the starting material.” Therefore, the complete manufacturing process from collecting the mucosa, through intermediates to in-process controls and validation, must be described in Module 3 with “full traceability.”
The traceability and other specific requirements mean that procedures involving drug master files (DMFs) or Active Substance Master Files (ASMFs) are “not applicable to biological active substances.” “For the same reasons,” it explains, “the existence of a certificate of suitability of monographs of the European Pharmacopoeia is not sufficient for an LMWH or for a heparin sodium intermediate.”
Report Highlights Multilateral Regulatory Cooperation
A 2018 annual report just published by the Swiss agency mentions biosimilars only in the context of discussions around quality within an International Coalition of Medicines Regulatory Agencies (ICMRA) summit held in September last year.
The report also notes Swissmedic’s involvement in several bodies promoting multilateral regulatory collaboration on small-molecule generics, including around bioequivalence and quality through the International Pharmaceutical Regulators Programme (IPRP). In particular, it noted, the IPRP’s Quality for Generics working group had been working primarily on a pilot ASMF/DMF database.
A generic medicines work sharing trial (GMWST) had been discussed, the Swiss agency noted, both within the ACSS consortium of regulators from Australia, Canada, Singapore and Switzerland, as well as during the Drug Information Association (DIA) EuroMeeting held last year in Basel, Switzerland.