Biosimilars & Biologics
Key legal info on biosimilars & biologics in Czech Republic. Prepared in association with PRK Partners, a leading law firm in Czech Republic, this is an extract from The Pharma Legal Handbook: Czech Republic, available to purchase here for GBP 99.
1. Are biosimilar medicines considered the same as generic medicines in your country?
No, biosimilars are not regarded as generics of biological medicines. Czech legislation implements EU directives, and directly applicable EU regulations on biosimilars and biologics apply. EU legislation establishes that, due to the variability and complex manufacturing process of biologics and biosimilars, more information and studies are needed for approval of biosimilars in comparison to generics.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
We are not aware of any specific exclusions of biologic or biosimilar medicines from patentability. In order to obtain patent protection, all requirements stipulated by Czech law, in particular by Act No. 527/1990 Coll., on Inventions, Designs and Improvement Proposals, as amended, must be met. One of these requirements is novelty. Practically speaking, it may be that typical biosimilar medicines will not be considered sufficiently novel for patent protection. However, we believe the chances of patentability are better if it relates to some specific elements of the biosimilar, such as new formulations involving a biosimilar medicine or a new process for making a biosimilar. A precise expert assessment of these issues would be required in each specific case to provide a more definite opinion on patentability.
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?
Rules set out in the Regulation 726/2004 (“MPA Regulation”)1 apply to the marketing authorization of biosimilars.
Under the MPA Regulation all medicinal products developed by specified biotechnological processes must obtain a centralized marketing authorization, in accordance with the MPA Regulation, before being put on the EU market. The relevant biotechnological processes are: (i) recombinant DNA technology, (ii) controlled expression of gene coding for biologically active proteins in prokaryotes and eukaryotes, including transformed mammalian cells, and (iii) hybridoma and monoclonal antibody methods.
In the event that a biosimilar is not developed by any of the processes specified above (e.g. naturally derived biologicals) a centralized marketing authorization is not mandatory. Nevertheless, even then there are two options when it is possible to apply for a centralized marketing authorization.
The first option applies to biosimilars where the reference medicinal product has already been authorized through the centralized procedure. These may be awarded centralized marketing authorization if they fulfil the requirements defined in the MPA Regulation as well as requirements arising from Directive 2001/83 (“Directive 83”)2.
The second option applies if the applicant is able to show that (i) the biologic constitutes a significant therapeutic, scientific or technical innovation or (ii) that the granting of the marketing authorization is in the interests of patients’ health at the EU level. The European Medicines Agency (the “Agency”) determines whether a biologic constitutes a significant therapeutic, scientific or technical innovation. Similarly, the Agency evaluates the level of patients’ health interest (factors to consider include, for example, whether the biosimilar addresses a specific health issue).
Additionally, as the centralized marketing authorization is not mandatory in these cases, other means of registration can be used instead. These are national registration, mutual recognition procedure and decentralized procedure.
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?
In general, less data is required for biosimilars in comparison with original biologics. This is because, rather than establishing the properties of a biosimilar on its own, the documentation provided to obtain approval for a biosimilar is to establish and prove its similarity to the reference biologic so that the proven safety and efficacy properties of the original biologic apply to the biosimilar as well. Additionally, the main aim of the process is to identify possible differences between the original biologic and the biosimilar or rather ensure that there are none, or only those that can be justifiably accepted.
The data required are comparable to the data required for a marketing authorization of other medicinal products. However, in particular, the results of pre-clinical and clinical studies must also be provided if the biosimilar in question does not fulfil the criteria of a generic, as set out in Directive 83.
Given the differences between individual biologics and biosimilars, the required data package differs case-by-case. It is therefore advisable to consult the relevant authority in advance.
5. What are the requirements for the choice of the reference comparator product?
The reference medicinal product must be an EEA-authorized medicinal product. Only one reference medicinal product can be used for the comparability program for quality, safety and efficacy studies during the development of a biosimilar.
Furthermore, in order to be able to use the reference medicinal product documentation in an application to register a biosimilar, the data exclusivity period for the reference medicinal product in question must have expired by the time the application for the biologic is submitted.
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
A non EEA authorized version of the reference medicinal product can be used only for certain studies (e.g. certain clinical and in vivo non-clinical studies) in order to avoid their unnecessary repetition, or alongside a reference medicinal product authorized in the EEA.
However, such non EEA reference medicinal product must be authorized by a regulatory authority with similar standards as the EMA (e.g. authorities participating in the International Council for Harmonisation (ICH)).
Furthermore, the applicant must demonstrate that the non-EEA medicinal product is representative of the EEA reference medicinal product based on scientifically justifiable comparative data, which compare all three medicinal products, i.e. both the EEA-authorized and non EEA-authorized medicinal product, as well as the biosimilar in question. The data needed to provide sufficient scientific justification differ case-by-case; however, they must be assessed along with the application for authorization of the biosimilar; it is therefore advisable to consult the relevant authority in advance.
7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
The most common method of price regulation is regulation by the maximum price. The maximum price is set in administrative proceedings conducted by the State Institute for Drug Control (“SÚKL”).
The maximum price of a medicinal product is established based on an average of the three lowest manufacturers’ prices in the countries of the reference basket. If the prices of the medicinal product in three countries of the reference basket are not available, then the price can be established based on an agreement between the marketing authorization holder (“MAH”) and a public health insurer (provided the agreement had been entered into in writing, in the public interest and after the defined negotiation procedure). If this method is not possible, then the maximum price is determined based on the closest therapeutically comparable medicinal product available in the Czech Republic, provided that the comparable medicinal product’s price had been determined on the basis of average manufacturers’ prices, as described above. If that method is not possible, then the closest therapeutically comparable medicinal product with the lowest price is found within the reference basket countries.
The maximum price of the very first medicinal product similar to the first medicinal product in a reference group (see below) is established by lowering the price established for the original biologic by 30 percent.
8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
In order for any medicinal product to receive reimbursement it must be authorized first (or approved for use in a specific treatment program). Additionally, if the medicinal product is subject to price regulation, its maximum price must be established first or along with the setting of the reimbursement.
Currently, Czech regulation does not provide any specific rules for the reimbursement of biologics; therefore, the general rules on reimbursement apply.
For the purposes of reimbursement, every medicinal product must be placed into a reference group. Each reference group includes therapeutically interchangeable medicinal products with comparable or close efficacy and safety and similar clinical use; the reason for this is that similar medicinal products should receive a similar level of reimbursement. The list of all reference groups can be found in a decree issued by the Czech Ministry of Health3. However, as not all medicinal products can be placed in these groups, additional “pseudo-reference groups” are often established for medicinal products with unique or new substances. The reimbursement procedure is similar to the one used for the reference groups.
Each reference group has its basic reimbursement. The basic reimbursement is (most commonly) established by using a medicinal product which belongs to the group and is available in the EU and the Czech Republic. The basic reimbursement of the reference group is then set in accordance with the price for the medicinal product with the lowest manufacturer’s price for a defined daily dose (DDD). The SÚKL then uses the basic reimbursement to determine the reimbursement of any medicinal product belonging to the group (and it is set based on the DDD content of that medicinal product).
Additionally, the SÚKL may establish specific conditions for reimbursement (e.g. prescription or indication restrictions). These do not prohibit doctors from prescribing the medicinal product; however, if the conditions are not met, the product will not be reimbursed.
Reimbursement for any biosimilar follows the same set of rules, except for the very first similar product in the relevant reference group (if this product is a biosimilar, then in addition the MAH must undertake to provide the biosimilar to the market for 12 months from the time it obtains the reimbursement). The reimbursement of the first similar product follows the price of the product to which it is similar and is subsequently lowered by a defined percentage (30 percent for biologics). The introduction of the first biosimilar product also results in lowering the basic reimbursement of the relevant reference group by 15 percent.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Yes. As described above, introduction of the first biosimilar in the reference group may result in lowering the basic reimbursement of that group by 15 percent.
More significantly, a MAH may negotiate with health insurers on the reimbursement of its medicinal product (e.g. original biologics) provided, in particular, (i) the resulting price for the patient is lower than the one which would have been determined by SÚKL in a proceeding, (ii) all health insurers are a party to the agreement and (iii) the agreement relates to all supplies of the medicinal product on Czech market. In this case, reimbursement of the medicinal product is equal to the price negotiated.
Such negotiations between the MAH and health insurers may therefore affect the basic reimbursement of the relevant reference group.
Furthermore, the SÚKL is entitled by law to conduct reimbursement reviews – either in-depth reviews at least every five years or abbreviated reviews – which affect reimbursement as well. An abbreviated review can be initiated by the SÚKL itself or by any health insurer at any time, so long as the expected yearly savings on health insurance expenditures are CZK 30 million or more (approx. EUR 1.1 mil.). The shortened review affects the entire reference group.
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?
Prescribing and dispensing practices are not regulated at the EU level; they fall under the responsibility of individual member states.
In general a physician is responsible for the treatment of a patient, including prescribing medicines. A physician is free to choose any medicinal product he/she believes is the most suitable for the patient, so long as the treatment falls within his/her specialization (e.g. oncology, rheumatology, etc.; moreover, some medicinal products can only be prescribed by physicians working in specialized hospital centers).
A duly specialized physician can therefore, with the patient’s consent, in theory switch from a biologic to a biosimilar, or even from a biosimilar to another biosimilar. However, in practice this approach is not at all recommended, mainly due to differences among biologics and biosimilars. For example, the Czech Society for Oncology recommends a cautious approach, even when the switch is required by circumstances (i.e. a patient’s intolerance to a specific medicinal product). It further recommends duly explaining to the patient, with duly justifying the switch in the health documentation, and even obtaining informed consent from the patient.
There is no specific standalone legislation for dispensing biologics or biosimilars; therefore, general rules apply. However, in practice, most pharmacies do not have biologics or biosimilars available – mainly due to their cost and only specialized pharmacies at specialized health centers are able to provide biologics or biosimilars. Usually, centers with specialized physicians do have their own pharmacies.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
There is no specific regulation when it comes to switching biologics or biosimilars. In general, the physician decides on what medicinal product will be prescribed to a patient. Thus, the physician can decide whether or not to switch a medicinal product with the patient’s consent. In some areas, such as rheumatology switching from an original biologic to a biosimilar is common. However, there is an ongoing discussion about the effects of switching, multiple switching, the so-called nocebo effects, etc. For these reasons, while not prohibited, for example, multiple switching is definitely not common.
Concerning pharmacy-level substitution, pharmacists may in general inform the patient about possible alternative medicinal products (which must be interchangeable, with similar efficacy and safety, etc.). The pharmacist may then dispense a substitute medicinal product if the patient agrees.
However, the Czech Chamber of Pharmacists does not recommend substitution when it comes to biologics (or biosimilars) due to differences among the products. Any possible substitution should be consulted with the prescribing physician and duly monitored. In practice, such substitution happens only very rarely in pharmacies, in specialized centers, in situations when the biologic or biosimilar prescribed is not available at the moment.
For the sake of completeness we add that any physician, when prescribing, may include the note: “do not substitute” (in Czech: “nezaměňovat”) to a prescription. In this case the pharmacist must dispense only the medicinal product prescribed.
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?
There is no biologics – or biosimilars – specific standalone legislation relating to post-authorization requirements. Thus, the general rules for medicinal products apply, including pharmacovigilance post-authorization processes.
However, there are some notable specifics for biologics and biosimilars. Concerning pharmacovigilance, most biologics and biosimilars approved by the Agency are in accordance with the MPA Regulation published (alongside other specific medicinal products) in the “List of medicines under additional monitoring”. As the name of the list suggests, these medicinal products are under additional monitoring from relevant regulatory authorities. In order to indicate their special status, the package leaflet as well as the summary of product characteristics is marked with a black inverted triangle accompanied by a short explanatory sentence and the statement: “This medicinal product is subject to additional monitoring”.
To name a few of the general obligations arising from, in particular, the MPA Regulation, the Agency may e.g. impose an obligation on the MAH to conduct a post-authorization safety study or post-authorization efficacy study, or it may request the MAH to provide data demonstrating that the risk-bene-fit balance of the medicinal product remains favorable, etc. Similar powers are vested in the Czech regulator, the SÚKL, in connection with national registration procedures.
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?
As described in our response to question no. 12, most biologics and biosimilars approved by the Agency are included in the “List of medicines under additional monitoring”. This status is indicated in the package leaflet, as well as in the summary of product characteristics of such medicines, with a black inverted triangle accompanied by a short explanatory sentence and the statement: “This medicinal product is subject to additional monitoring”. Aside from that, there are no special requirements with regard to the labelling of biosimilar medicines.
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)
There have been no such recent developments in relation to biosimilars in the Czech Republic.
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?
There are ongoing discussions on possible changes to medicinal product regulation (including biologics and biosimilars and rules for their prescription, etc.). Thus far, nothing specific concerning biosimilars has been proposed.
(1) Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Union procedures for the authorization and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
(2) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use
(3) Decree No. 384/2007 Coll., on the list of reference groups.