Legal & Regulatory > Romania > Biosimilars and Biologics

The ins and outs of biosimilars and biologics in Romania. Prepared in association with Mușat & Asociații, a leading global law firm, this is an extract from The Pharma Legal Handbook: Romania, available to purchase here for GBP 75.

1. Are biosimilar medicines considered the same as generic medicines in your country?

The biosimilar medicinal products are not considered the same as generic medicinal products, since the Romanian legislation regulates in a different manner biosimilars and generics.

As per the local legislation, a biosimilar is a biologic medicinal product similar to another already authorised biologic medicinal product, referred to as the biologic reference medicine. Thus, the biosimilar is not identical to its reference product.

2. Are all biologic medicines, including biosimilar medicines, patentable in your country?

According to the Romanian Patent Law, in order to be subject matter of a patent, biotechnological inventions have to first comply with the general conditions of a patentable invention. There are no specific exceptions provided by the Patent Law concerning the patentability of biologic or biosimilar medicines.

However, in the biotechnology field, the Patent Law draws the limits of patentability of biotechnological inventions, by indicating which inventions are patentable and by providing a list of exceptions thereto. Therefore, inventions that concern a product consisting or containing biological material or a process by means of which biological material is produced, processed or used, to be patentable should:

1. be new, involve an inventive step and susceptible of industrial application;
2. refer to one of the specific subject matters established by the legal provisions:

1. 1. biological material which is isolated from its natural environment or produced by means of a technical process may be the subject of an invention even if it previously occurred in nature;
   2. plants or animals if the technical feasibility of the invention is not confined to a particular plant or animal variety;
   3. microbiological or other technical process or a product, other than a plant or animal variety, obtained by means of such a process;
   4. an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, even if the structure of that element is identical to that of a natural element;

3. not be excepted from patentability by the Patent Law, as follows:

1. 1. the human body in various stages of its formation and development, as well as the mere discovery of one of its elements including the sequence or a partial sequence of a gene;
   2. processes for cloning human beings;
   3. processes for modifying the germ line genetic identity of human beings;
   4. uses of human embryos for industrial or commercial purposes, assuming that they do not have a therapeutic or diagnostic purpose applied to the human embryo, if useful for the same;
   5. processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes.
   6. plant and animal varieties.
   7. essentially biological processes for the production of plants or animals.

Hence, provided that the above provisions are observed, starting from the general conditions (i.e., being novel, having an inventive step and being capable of industrial application), to the specific ones, biologic or biosimilar medicines may be subject to patentable inventions, both for product and for process inventions.

If in case of biological innovative medicinal products the patentability can be more easily established, the biosimilar medicinal products might require a clarification in this respect, taking into consideration that they are highly similar to another already approved biological medicine and require comprehensive comparability studies with the reference biological medicine. Such similarity between the biosimilar product and the reference one does not remove ab initio the novelty and the inventive step of the biosimilar. Even if the latter one is a subsequent version of an existing biologic drug, however it is not an exact copy of the reference medicine, and there might be cases when the biosimilar medicine can fulfil the conditions of patentability even for a product invention, not only for a process invention. Only if the claims for the biosimilar medicine invention are not found in the state of the art, meaning they exceed the protection granted for the reference biological medicine, the protection conferred by a patent for such biosimilar medicine could be granted, irrespective if the protection is for the product itself or for a process regarding such product.

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?

As a rule, the marketing authorisation of the biosimilar medicines should be approved by the European Medicines Agency at centralized level.

The Romanian legislation does not provide for a specific regulatory framework for the marketing authorization of biosimilar medicines at the national level.

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 authorisation of biosimilars products in the EU requires a different set of data compared to other biologicals. In the case of biosimilars, applicants should provide a special data package proving the high similarity with the reference product. Such a data package is obtained by performing a biosimilar comparability exercise.

The Romanian Health Law mentions the need to submit the results of appropriate pre-clinical tests or clinical trials when a biological medicinal product does not meet the conditions to be qualified as a generic medicine. The differences between the biological reference medicine and the biosimilar could relate to raw materials, manufacturing processes, etc. However, the results of other tests and trials from the reference medicinal product’s dossier should not be provided.

5. What are the requirements for the choice of the reference comparator product?

As per the European Medicine Agency’s Guidelines on similar biological medicinal products, the reference medicinal product should be a medicinal product authorized in the EU, based on a complete dossier in accordance with Directive 2001/83/EC on medicinal products for human use.

6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?

In principle, the reference medicinal product used as a comparator should be a medicinal product authorised in the EEA. However, it is also possible for the applicant to compare the biosimilar with a non-EEA authorised comparator (i.e., a non-EEA authorised version of the biological reference medicinal product), authorised by a regulatory authority with similar scientific and regulatory standards as the EMA.

In this respect, European Medicine Agency’s guidelines mention that if certain clinical and in vivo non-clinical studies are performed with the non-EEA authorised comparator, the applicant for the marketing authorisation should provide adequate data or information to scientifically justify the relevance of these comparative data and establish an acceptable connection with the EEA-authorised reference product.

7. How are the prices of biosimilar medicines regulated? Is this any different from the requirements for the original Biologics drug?

The prices of biosimilar medicines should be approved by the Ministry of Health, based on the application dossier submitted by the marketing authorisation holders or their representative. As a rule, the price proposed by the applicant for a medicinal product should be lower than or equal to the prices of the same medicine in the 12 (twelve) reference countries mentioned under section 9 above (i.e., Czech Republic, Bulgaria, Hungary, Poland, Slovakia, Austria, Belgium, Italy, Lithuania, Spain, Greece and Germany).

The pricing norms provide for different rules for reference (original) biological medicines and for the biosimilar medicines, as follows:

1. from a pricing perspective, the reference (original) biological medicines are assimilated to innovative medicines;
2. as a rule, the price of biosimilars medicines should not exceed the biosimilar reference price (BRP), computed at the level of 80% of the price of the original biological medicine;

It is noteworthy that this rule applicable to biosimilars is more favourable than the pricing rule applicable to generic medicines. Thus, the price of generics should not exceed the generic reference price (GRP), representing 65% of the price of the innovative product.

The latest amendments to the pricing legislation in Romania provide for an exception to the rule of proposing the price for the biosimilar medicines by reference to the biosimilar reference price, if a medicinal product is the only medicine having the respective INN, strength and pharmaceutical form included in the CANAMED national price catalogue.

In such cases, the price proposed to the Ministry of Health does not have to be compared to the biosimilar reference price, but only to the price in the 12 reference countries.

8. What is the reimbursement policy for biosimilar medicine? Is this any different from the requirements for the original Biologic drug?

The national legislation contains special rules providing for the reimbursement and prescribing of biosimilars, as follows:

1. there are special criteria for the health technology assessment of biosimilars performed by the National Agency of Medicines and Medical Devices in order to evaluate if the product could be included in the national list of reimbursed medicines;
2. while the general rule is that the medicines should be prescribed by mentioning their international non-proprietary name (and not the trade name) on the medical prescription, the attending physicians are entitled to prescribe biological medicines, including biosimilars, by mentioning their trade name on the prescription;
3. (medicines suppliers, namely open-circuit pharmacies which have concluded agreements with health insurance houses for the supply of medicines and medical supplies granted for the out-patient treatment of patients included in certain national health programs within the social health insurance system, are required not to replace a biological with its biosimilar, without the physician’s recommendation.

9. Does biosimilar competition impact the reimbursement policy of the originator reference products?

Yes, if a biosimilar product is placed on the Romanian market and becomes reimbursed in the Romanian health insurance system, this will impact the reimbursement of the originator reference product. Amongst others, the reimbursement price of the originator reference product (i.e., the value reimbursed by the National Health Insurance House) will be reduced

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?

The national legislation does not expressly provide for special requirements for prescribing and dispensing biosimilar medicinal products, except that the biosimilars and the original biological medicines could be prescribed by mentioning their trade name on the prescription. The general rule, applicable to all other medicines, is that the prescription should only mention the product’s international non-proprietary name (INN) and not the trade name, and that the pharmacy could dispense any medicine having the respective INN.

Otherwise, the biological medicines (originals or biosimilars) could be released to patients by open-circuit pharmacies or by hospitals (closed-circuit pharmacies), depending on the prescription requirements and the therapeutic protocols applicable to each product.

There are no differences between the original biologics and the biosimilars, as regards the prescription and the dispensing to patients.

11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?

The process of replacing one medicine for another one known to have the same clinical effect (e.g., replacing a biological reference with a biosimilar or vice-versa or replacing a biosimilar with another) is known as interchangeability. Interchangeability can be performed either by:

1. switching – the process of replacing one medicinal product with another, performed by the prescribing physician; or
2. automatic substitution – the process of dispensing another medicinal product instead of the one mentioned in the medical prescription, performed at pharmacy level by the pharmacist, without consulting the prescribing physician.

According to the recommendations at European level, the decision on whether to allow interchangeable use of such medicinal products belongs to each EU Member state.

In this respect, the Romanian legislation mentions that switching from a biological reference medicinal product to a biosimilar medicinal product (or from a biosimilar to another one) should be decided only by the physician.

Moreover, the national reimbursement legislation provides for the obligation of pharmacists to dispense biologicals (including biosimilars) having the exact trade name provided for in the medical prescription. The automatic substitution of biologicals (including biosimilars) at pharmacy level, without the physician’s approval, is expressly prohibited.

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 legislation does not expressly provide for a special pharmacovigilance system for biosimilar medicinal products, hence they are subject to the same pharmacovigilance requirements as all biologicals.

However, note should be made that the applicant for a marketing authorisation intended for a biosimilar should include in the application a description of the pharmacovigilance system as part of a risk management plan due to be implemented for the respective medicinal product.

As for the post-authorisation requirements, applicants/marketing authorization holders should take into account the following obligations:

1. the potential obligation to carry out post-authorization safety studies; if such studies have been requested for a reference medicinal product, they shall be generally requested for its biosimilar as well;
2. the obligation to submit with the regulatory authorities periodic safety update reports;
3. the obligation to ensure product traceability; in this respect, it is essential to identify the product with the trade name or INN, as well as the name of the marketing authorization holder, and batch number of the product administered; for this exact reason biological medicines shall be prescribed by physicians by their trade name and not by their INN;
4. the obligation to ensure a monitoring system specially designated for biologicals; such monitoring system is called “additional monitoring” and biologicals are hence included on a list of medicinal products under “additional monitoring”; the list includes products authorized in the EU which are closely monitored by the regulatory authorities (due to the fact that their active substance is new on the market or due to the limited data on its long-term use) and which are labelled with a black triangle on their package insert, along with the sentence “This medicinal product is subject to additional monitoring”.
5. the obligation to monitor immunogenicity, in order to analyze rare immune reactions which can only be detected after a long follow-up period in larger numbers of patients.

13. Are there specific policies and requirements for labelling biosimilar medicines in the event of second medical use patents? Is this any different from the requirements for the original Biologic drug?

The labelling of biosimilars follows the general legal framework providing for the labelling of medicinal products.

Additionally, it is mandatory that the biosimilar’s label does not infringe the intellectual property rights of the original biological product.

In this respect, EMA’s procedural advice for users of the centralized procedure for similar biological medicinal products applications refers to the “skinny labeling” of biosimilars, which means that information directly related to a patented therapeutic indication should be deleted from the following sections: therapeutic indications, posology and method administration and pharmacodynamics properties of the summary of product characteristics.

From a reimbursement perspective, by way of example, if the biosimilar will first be included only in certain sub-lists of the INN Reimbursement List (i.e., only for certain therapeutic indications), it could apply at a later stage (e.g., once it becomes free to enter the market with full label) for the reimbursement of the remaining indications.

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)

According to the latest information published by the Ministry of Health and by the National Health Insurance House, roughly 26 biosimilars (trade names) were placed on the Romanian market during 2020, out of which 25 biosimilars were reimbursed in the national health insurance system. Additional biosimilars might be placed on the Romanian market in the following period.

In July 2020, the Ministry of Health issued an order for approving new HTA evaluation criteria, which provides certain favourable rules for biosimilars, making it easier for biosimilar products to become reimbursed in the national health insurance system.

In January 2020, the Romanian Competition Council sanctioned Roche with fines amounting to roughly EUR 12,800,000 for an alleged abuse of a dominant position on the oncology market. According to the press release issued by the Competition Council, the actions of Roche Romania company created certain barriers to market entry, delaying the access of biosimilar alternatives.

From an IP standpoint, in the last years, there were several disputes regarding the adequate labelling and promotion in Romania. The manufacturers of original biologics stressed that the biosimilars should be labelled, promoted, reimbursed, sold and acquired without breaching the intellectual property rights of the originals and that the requirements concerning “skinny labelling” should be observed.

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 healthcare authorities announced their intention to identify the most appropriate solutions for encouraging the market access of biosimilars, since this will bring significant cost savings for the national health insurance system. However, it is difficult to anticipate when these changes will be introduced in the legislation.