Biosimilars and Biologics
Key legal info on biosimilars & biologics in Denmark. Prepared in association with Gorrissen Federspiel, a leading law firm in Denmark, this is an extract from The Pharma Legal Handbook: Denmark, available to purchase here for GBP 75.
1. Are biosimilar medicines considered the same as generic medicines in your country?
A biosimilar medicinal product is a new version of an existing biological medicinal product (i.e. a medicinal product is derived from a biological source). Biosimilar products are developed by establishing i) a therapeutic effect, ii) a safety profile, and iii) a stability profile that is similar to the reference biological medicinal product. However, since biological medicinal products have a more complex molecular structure than chemically produced medicinal products (non-biological products), biosimilar medicinal products are not identical to their reference product and may exhibit minor differences in the molecule in relation to the reference medicinal products.
By comparison, generic medicinal products are “copies” of small molecule medicinal products (medicinal products that are normally produced by way of chemical synthesis), in the sense that the medicinal product must have the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product. The bioequivalence with the reference medicinal product must have been demonstrated by appropriate studies.
Due to the nature of generic medicinal products, an abridged procedure is available for marketing authorizations for generic medicinal products. The Danish legislation implements the applicable EU directives on medicinal products, in including the rules on the abridged procedure, which means that applicants for generic medicinal products will not be required to provide the results of pre-clinical tests and clinical trials if it is possible to demonstrate that the medicinal product is a generic of a reference medicinal product that is or has been authorised for not less than eight years in a country of the EU/EEA.
In principle, the abridged procedure is also available to biosimilar medicinal products. However, because it is not possible to manufacture an identical biological medicinal product, biosimilar medicinal products are subject to more restrictive and stringent regulatory requirements with regard to clinical studies.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
Yes, provided the general patentability requirements are met (the three main criteria being novelty, industrial application, and inventiveness).
Naturally, as biosimilar medicinal products are new versions of existing biological medicinal products, it may be more difficult to establish that the patentability requirements are met for biosimilar products.
3. Is there a specific regulatory framework for the marketing authorization of biosimilar medicines in your country? If yes, what is the regulatory framework for the authorization of biosimilar medicines?
No, there is no specific regulatory framework for the marketing authorisation of biosimilar medicinal products in Denmark.
Biological medicinal products must as a starting point be approved by the European Commission under the centralised procedure in case the biosimilar medicinal product is produced by biotechnological processes. The European Medicines Agency (the “EMA”) has issued a number of guidelines on biological medicinal products to assist developers prepare marketing authorisation applications.
The Danish Medicines Act and secondary legislation issued under this act do not contain substantially different provisions on the authorisation of biological medicinal products.
As a starting point, biosimilar medicinal products are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines.
The relevant EU legislation provides that derogations from the requirements for a full marketing authorisation may be made for generic and biosimilar medicinal products. However, if a biosimilar medicinal product does not meet the conditions in the definition of generic medicinal products due to differences in raw materials or differences in manufacturing processes of the biosimilar medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The relevant supplementary data that may be required is set out in Annex I of Directive 2001/83/EC.
4. What kind of data package is needed to obtain approval for a biosimilar drug? Is this any different to the requirements for the original Biologics drug?
The main objective when assessing applications for biosimilar medicinal products is to determine the similarity of the reference biological medicinal product to the biosimilar medicinal product. According to the EMA, the comparability exercise should be a robust head-to-head comparison between the similar biological medicinal product and the reference medicinal product performed at the levels of quality, safety and efficacy.
Annex I of Directive 2001/83/EC provides that the information to be supplied in order to establish the comparability will be determined on a case-by-case basis in accordance with the EMA’s scientific guidelines. Thus for example, both pharmaceutical, chemical and biological data, supplemented with bio-equivalence, bio-availability data, and toxicological and other non-clinical and appropriate clinical data must be provided.
5. What are the requirements for the choice of the reference comparator product?
The reference medicinal product must have been authorised under Article 6 of Directive 2001/83/EC (based on a complete dossier) for not less than 8 years in a Member State or in the Union.
The EU legislation provides that an application for marketing authorisation of a biosimilar medicinal product can be submitted after expiry of the data exclusivity period for the reference biological medicinal product (i.e. 8 years after the date of notification of the authorisation of the reference medicinal product, cf. Article 14(11) of Regulation (EC) No 726/2004).
However, the biosimilar medicinal product cannot be placed on the market until the 10 years (or 11 years) of market exclusivity of the reference biological medicinal product have expired.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
The reference medicinal product must have been authorised under Article 6 of Directive 2001/83/EC for not less than 8 years in an EU member state or in the European Union.
However, the EMA has published procedural advice for users of the centralised procedure for similar biological medicinal products applications, which provides that it may be possible for an applicant for a marketing authorisation of a biosimilar medicinal product to compare the biosimilar medicinal product in certain clinical studies and in in vivo non-clinical studies (where needed) with a non-EEA authorised version of the reference medicinal product.
The non-EEA reference medicinal product must be authorised by a regulatory authority with similar scientific and regulatory standards as EMA.
The EMA’s guidance provides that it will be the applicant’s responsibility to establish that the batches sourced outside the EEA is representative of the reference medicinal product authorised in the EEA through an extensive analytical comparison.
7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
The Danish Medicines Act and secondary legislation issued under this act do not contain substantially different provisions on pricing of biosimilar medicinal products.
At manufacturing level, the company placing the medicinal product on the market (or the importer of the medicinal product) is free to determine the prices for prescription medicinal products when selling to wholesalers, pharmacies and/or other authorised retail sellers.
It should be noted, however, that the Danish Association of the Pharmaceutical Industry on behalf of its members have entered into agreements with the Danish Ministry of Health and the Danish Regions which introduce so-called “price ceilings” for medicinal products used in the hospital sector and for medicinal products eligible for reimbursement.
8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
The Danish Medicines Act and secondary legislation issued under the Medicines Act do not contain substantially different provisions on reimbursement of biological and biosimilar medicinal products.
In Denmark, the DKMA decides on the reimbursement status of each medicinal product. The DKMA determines what medicinal products are eligible for reimbursement based on an application from the company placing a medicinal product on the market. The DKMA may determine that reimbursement should be conditional, e.g. on it being prescribed to certain patient groups or specific diseases.
The DKMA may establish so-called substitution groups/reimbursement groups of medicinal products with the same indication and comparable treatment effects, for the purpose of calculating the same reimbursement price for all medicinal products within the same reimbursement group. For medicinal products within a reimbursement group, the applicable reimbursement price will be the cheapest medicinal products in the group. The purpose of the system is to encourage patients to purchase the most inexpensive medicinal product available.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
As described in question 8 above, the DKMA decides on the reimbursement status of medicinal products, and also determines whether to establish substitution groups. For medicinal products within a substitution/reimbursement group, the applicable reimbursement price will be the price of the cheapest medicinal products in the group. The purpose of the system is to encourage patients to purchase the most inexpensive medicinal product available.
Therefore, if the DKMA establishes a substitution group for certain biological medicinal products, and the cheaper biosimilars are entered into this group, then this would most likely influence the price of the reference biological medicinal product. However, as described in question 11 below, there is not a clear-cut policy on substitution of biological medicinal products under Danish law.
10. What is the legal framework for biosimilar medicines prescribing (clinical decision maker) and dispensing (pharmacy level, hospital or retail)? Is this any different to the requirements for the original Biologics drug?
In Denmark, a pharmacy must always offer the cheapest “synonymous” medicinal product to the patient, unless the patient’s physician has indicated otherwise on the patient’s prescription.
However, physicians have discretion to prescribe the biologic or biosimilar versions of medicinal products, and, as described in further detail in question 11 below, there is no clear-cut Danish regulation regarding substitution of biologics and biosimilar medicinal products. Therefore, pharmacists are as a starting point not permitted to switch patients from biologics to biosimilar medicinal products.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
The system is based on physician-led switching.
The EMA does not regulate interchangeability, switching and substitution of a reference biological medicinal product by its biosimilar. The substitution of medicinal products is regulated on national level.
In Denmark, the DKMA determines whether a biological medicinal product and a biosimilar medicinal product are suitable for substitution. Danish legislation does not provide a definitive answer on whether biological medicinal products and biosimilar medicinal products are suitable for substitution.
The previous Danish Council for the Use of Expensive Hospital Medicines (“RADS”, which has now been replaced by the Danish Medicines Council) has expressed its opinion that reference biological medicinal products are suitable for substitution without further consideration. It seems the Danish Medicines Council also believes patients can be switched from a biologic/originator medicine to a biosimilar medicine as the biosimilar medicines should not deviate from the reference biologic medicine when it comes to efficacy, safety and quality.
However, this opinion has been countered by the Danish Association of the Pharmaceutical Industry (“Lif”). In Lif’s opinion, there is no basis for automatic substitution of biological medicinal products and biosimilar medicinal products.
Likewise, the Danish Institute of Rational Pharmacotherapy (an institute established under the Danish Health Authority) has expressed that automatic and frequent switching between biosimilar medicinal products would be inappropriate and should be avoided.
On the EU level, the EMA has underlined that there may be differences between the reference biological medicinal product and the biosimilar product, and that any switching should be carried out with due caution.
Therefore, biological medicinal products and biosimilar medicinal products are as a starting point not suitable for pharmacy-level substitution.
12. What are the post-authorisation requirements (including pharmacovigilance, risk management plans, post-approval studies) for biosimilar medicines? Is this any different to the requirements for the original Biologics drug?
The Danish Medicines Act provides that the holder of a marketing authorisation must, i) keep records of suspected adverse reactions, ii) make such records available to the DKMA, iii) report information on adverse reactions to the DKMA, and iv) prepare and submit periodic safety update reports to the DKMA.
The DKMA oversees and monitors the rules on pharmacovigilance. To this end, the DKMA handles and analyses adverse reaction reports from citizens, healthcare professionals and the industry. The DKMA also conducts routine inspections both with respect to pharmacovigilance, adverse reaction reporting and quality management.
As part of its pharmacovigilance system, the DKMA conducts scientific evaluations of the benefit-risk balance of the medicinal products based on the information submitted to it. The DKMA determines whether it is necessary to implement safety measures, and may also decide to change, suspend or withdraw a marketing authorization if the benefit-risk balance calls for it.
The DKMA’s pharmacovigilance system also covers biosimilar medicinal products, and the post-authorisation requirements for biosimilar medicines are substantially identical to the requirements for other medicinal products.
However, the DKMA currently has increased focus on the monitoring of adverse reactions concerning biological (and biosimilar) medicinal products, including such reactions as may occur when switching between biosimilar medicinal products and the reference medicinal products.
Therefore, biological products are monitored on a product-by-product level, and, there are specific requirements applicable when reporting adverse reactions in connection with biological products. For example, the Danish Executive Order on reporting of side effects on medicinal products, etc. (Executive Order no. 1823 of 15 December 2015), provides that an adverse reaction report from a doctor, dentist or midwife must, to the extent possible, include the name and batch number of the medicinal product if the report concerns a biological medicinal product appearing from the list made by the DKMA (the list can be found on the DKMA’s website).
13. Are there specific policies and requirements in terms of biosimilar medicines labelling in the event of second medical use patents? Is this any different to the requirements for the original Biologics drug?
A biological (or biosimilar) medicinal product, for which there is limited post-marketing experience (e.g. if approved after 1 January 2011), is subject to additional monitoring. Such medicinal products must be marked with a black triangle in the summary of product characteristics (“SmPC”) and the package leaflet together with an explanation and an encouragement to report side effects.
The labelling of biosimilar medicinal products is currently governed by the EMA’s QRD guidance “general principles regarding the SmPC information for a generic/hybrid/biosimilar product” dated June 2018. This guidance does not distinguish between biosimilar medicinal products and generics products in terms of labelling.
Pursuant to the guidance, the SmPC content for a hybrid or biosimilar medicinal product has to be consistent with the reference medicinal product for the common information applicable to the hybrid or biosimilar product, meaning that the information from the reference medicinal product’s SmPC that applies to the biosimilar medicinal products should be included in the SmPC of the biosimilar medicinal product.
The EMA’s approach is based on an assumption that the labelling of a biosimilar medicinal product should be identical to that of the reference biological medicinal product. However, as is also expressed by EuropaBio (Europe’s largest and most influential biotech industry group), as the development of each distinct biosimilar medicinal product requires generating specific pre-clinical and clinical data, there are ongoing deliberations on whether the labelling of the biosimilar medicinal products should include information on both the biosimilar medicinal product and the reference product.
14. Have there been any significant legal/judicial developments in relation to biosimilars in your country? (Including but not limited to IP, procurement, competition, misleading information campaign, access to reference comparator product)
Because the patent protection, data exclusivity and market exclusivity of the original biological medicinal products are starting to expire, new biosimilar medicinal products have entered onto the market in the most recent years. The introduction of new products has also given rise to judicial cases concerning patents involving biological medicinal products and biosimilar medicinal products. However, these cases are still of a relatively limited number.
15. Are there proposals for reform or significant change to the legal, regulatory, procurement of biosimilars? If yes, when are they likely to come into force?
The DKMA has emphasized the increased focus that the DKMA will have on biological and biosimilar medicinal products due to the increasing number of products in development and expiry of patent protection of the original biological medicinal products.
To ensure a targeted and product-specific monitoring of biological and biosimilar medicinal products, the DKMA and the Danish Ministry of Health have prepared an action plan on biological and biosimilar medicinal products (the action plan can be found on the DKMA’s website).