Biosimilar Drugs in Albania “current situation”

The use of biologicals is very important in the treatment of mild illnesses ranging from anaemia to life threatening cancers and neurological disorders. These biologics include products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues and recombinant therapeutic proteins [1]. However, increasing use of these effective therapies is limited by their costs and accessibility. The expiry of patents of these products created new opportunities for the development of similar biologics (biosimilars) that could offer comparable effective and quality healthcare at an affordable cost [2-4]. To achieve comparable quality, efficacy and safety to their respective originator biologicals, strict compliance with appropriate science-based regulatory standards is essential to approve a biosimilar product [4].


Introduction
The use of biologicals is very important in the treatment of mild illnesses ranging from anaemia to life threatening cancers and neurological disorders. These biologics include products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues and recombinant therapeutic proteins [1].
However, increasing use of these effective therapies is limited by their costs and accessibility. The expiry of patents of these products created new opportunities for the development of similar biologics (biosimilars) that could offer comparable effective and quality healthcare at an affordable cost [2][3][4]. To achieve comparable quality, efficacy and safety to their respective originator biologicals, strict compliance with appropriate science-based regulatory standards is essential to approve a biosimilar product [4].

Aim of the Review
To give a present situation of biosimilars and the originators authorized for Marketing in Albania. Issues regarding Law and Regulations, Reimbursement situation.

Legal Basis for Biosimilars in Albania
For the first time the definition Biosimilar was mentioned in Albanian legislation in 2014, Law No.105/2014, 31.07.2014 "On drugs and pharmaceutical service", amended: A biosimilar is a biological drug that is highly similar to another biological drug which already has a marketing authorization (reference biological product) and has the same active ingredient, dosage form and route of administration as the reference product, for which it is determined through a quality, safety and efficacy program.
This drug doesn't fulfill the criteria to be classified as a generic drug because it differs from the biological drug regarding the ingredients and manufacturing process and for these reasons is not substitutable [5]. The total fee, paid by the pharmaceutical company that has the exclusivity of a certain biosimilar (not an antitumoral one) for Albania is 800€ (100€ prepayment prior to application) and 700€ final payment, after the issuance of Order of Minister.
If the biosimilar is designed as an antitumoral drug than the total fee is 500€ (100€ prepayment prior to application) and 400€ final payment, the issuance of Order of Minister [5]. This means that the

Specific Features of Biosimilars According to EMA
Highly similar to the reference drug: The biosimilar has physical, chemical and biological properties highly similar to the reference drugs. There may be minor differences from the reference medicine which are not clinically meaningful in terms of safety or efficacy.
No clinically meaningful differences compared with the reference drug: No differences are expected in clinical performance. Clinical studies that support the approval of a biosimilar confirm that any differences will not have an effect on safety and efficacy. Variability of biosimilar kept within strict limits: Minor variability is only allowed when scientific evidence shows that it does not affect the safety and efficacy of the biosimilar [ Table 1]. The range of variability allowed for a biosimilar is the same as that allowed between batches of the reference drug. This is achieved with a robust manufacturing process to ensure that all batches of the drug are of proven quality.
Same strict standards of quality, safety and efficacy: Biosimilars are approved according to the same strict standards of quality, safety and efficacy that apply to any other drug [7]. Table 1: Compares development and characteristics of generics and biosimilars [7].

Generic Drugs Biosimilar Drugs
Usually produced by chemical synthesis Obtained from a biological source Generally possible to obtain exactly the same molecule Possible to reproduce the molecule to a high degree of similarity due to unique biomanufacturing methods and natural biological variability Mostly smaller molecules, easier to characterise In general, larger, structurally more complex molecules, which require multiple technologies for their characterisation Full data requirements on pharmaceutical quality Full data requirements on pharmaceutical quality, plus additional quality studies comparing the structure and biological activity of the biosimilar with the reference medicine Development based on demonstration of bioequivalence (i.e. that the generic and the reference medicine release the active substance into the body at the same rate and to the same extent under similar conditions) Development based on demonstration of biosimilarity using comparability studies (comprehensive head-to-head comparison of the biosimilar with the reference medicine to show high similarity in chemical structure, biological function, efficacy, safety and immunogenicity) Clinical data requirements are mainly pharmacokinetic bioequivalence studies In addition to comparative pharmacokinetic and pharmacodynamic studies, safety and efficacy data may be required, particularly for more complex biological medicines All indications approved for the reference medicine can be granted based on demonstrated bioequivalence, without the need for further clinical data Efficacy and safety have to be justified in each indication. However, confirmatory clinical trials with the biosimilar are usually not needed in every indication that has been approved for the reference medicine. After demonstration of biosimilarity, extrapolation of data to other indications is possible if the scientific evidence available addresses all specific aspects of these indications product. Importantly, due to the complexity of the process, different batches of a particular moAb could even be considered biosimilar versions of the moAb given they do not follow a purely chemical pathway but are made from living cells [8].

Authorized Biosimilars in Albania
There are 14 biosimilars (each of them with different dosage forms), (see

Important Parameters which Define Biosimilars
Indication Extrapolation: For prescribers, extrapolation is an extremely important component to the concept of bio similarity.

The EMA defines extrapolation as 'extending information and
conclusions available from studies in one or more subgroups of the patient population (source population) to make inferences for another subgroup of the population (target population), or condition or product, thus reducing the need to generate additional information… to reach conclusions for the target population [9].
For a biosimilar product to be approved, it is not always necessary to conduct clinical efficacy studies in every indication for which the reference drug was approved. The biosimilar must demonstrate that there are no clinically meaningful differences relative to the reference drug in a sensitive patient population i.e. a group of patients where any differences between the two drugs are most likely to be revealed. The scientific justification for extrapolation to other indications not studied in the biosimilar clinical programme is evaluated as part of the assessment process on a case-by-case basis, based on the totality of data (quality, non-clinical and clinical data).
In line with this the biosimilar may be approved in all indications for which the reference product is approved. This is referred to as indication extrapolation. It is an important concept for healthcare professionals to be familiar with, given that efficacy trials for the medicine may not have been carried out in all proposed treatment groups. However, extrapolation is based on scientific principles requiring specific structural, physiochemical and biological comparability data justifying its acceptance [9,10].

Interchangeability: Interchangeability between biosimilars
and reference products is an ongoing area of debate. While prescribing practices are at the discretion of healthcare professionals, it is not recommended that patients are switched back and forth between a biosimilar and the reference drug product.
It is recommended to have consultations between prescribers, pharmacists and procurement staff in relation to deciding on treatment preferences for using a reference or a biosimilar drug [9,10].

Pharmacovigilance and Adverse Drug Reaction Reporting:
Pharmacovigilance and monitoring of adverse events are usual components of the authorization process and use of any new drug, including biosimilars in Albania. As is the case for all biological drugs, the clinical safety of biosimilars must be monitored closely on an ongoing basis during the post-approval phase, including continued benefit-risk assessment. Any specific safety monitoring imposed on the reference drug or drug class will also apply to the biosimilar. Reporting of adverse reactions to drug authorities is mandated for marketing authorization holders in Albania. Adverse reactions are reported through a database maintained by the EMA known as Eudravigiilance. Healthcare professionals should also report any adverse reactions they are aware, near the Albanian Agency [9,[11][12][13].

Conclusion
As noted above, a biosimilar is not identical to the reference societies, pharmacists and patients -to the barriers and plausible solutions could help improve further uptake of biosimilars. It is hoped that with increased experience, some of these uncertainties and misgivings will be overcome.

Recommendations
Approaching the Albanian legislation with EU legislation and with the legislation of region countries regarding biosimilar drugs. Creating a data base on the extension of use of biosimilars in Albania. Creating new cooperation bridges with the relevant Agencies of other countries to share the experiences in the field of orphan medicines.