Biosimilars & Biologics
Biosimilars & biologics in Egypt – a legal guide. Prepared in association with Youssry Saleh Law Firm, a leading global law firm, this is an extract from The Pharma Legal Handbook: Egypt, available to purchase here for USD 99.
1. Are biosimilar medicines considered the same as generic medicines in your country?
In Egypt, Biosimilars are considered different from Generic Medicines but similar to biological products, where the “Biosimilar” definition according to the Guidelines for Registration of biosimilar products in Egypt, is the following: A similar biological medicinal product having the same active substances, dosage form, concentration and route of administration of a reference biological product and was proven through a comparability program that is quality, safety, and efficacy are highly similar to a reference product when prescribed on a claimed indication.
While the Generic is a copy of medicinal product with chemical, small molecule drug substance(s) that is/are structurally and therapeutically equivalent to that/those of and originator pharmaceutical product.
2. Are all biologic medicines, including biosimilar medicines patentable in your country?
Biological and biosimilar in Egypt are patentable in accordance with the Intellectual Property Law No.82 of the year 2002 in Egypt, the Patent was defined in Article 1 as follows: “A patent shall be granted, in accordance with the provisions of this Law, to any industrially applicable invention, which is new, involves an inventive step, whether connected with new industrial products, new industrial processes, or a new application of known industrial processes. The patent is also granted, independently, for any modification, improvement or addition to a previously patented invention, which meets the criteria of being new, inventive and industrially applicable, as stated in the preceding paragraph; in which case, the patent shall be granted, under the provisions of this Law, to the owner of the modification, improvement or addition.”
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?
Yes, there is a specific guideline issued along with Ministerial Decree No.150 of the year 2015, in order to regulate the authorization of the biosimilar is at the Central Administration Planning Administration CAPA Registration, there are two approaches for the registration of a biosimilar product:
- For the imported products: the finished product is manufactured and marketed in the country of origin and only evaluation of the final dossier is performed. The steps of registration are clarified below;
- For locally manufactured products: they are finished products manufactured in factories licensed in Egypt and include the following categories:
- Manufacturing finished product starting from developing active substances to the final finished product in local factory/factories;
- Manufacturing finished product starting from manufacturing the final formation from an imported active substance;
- Filling of an imported ready to fill final bulk.
The marketing phases of the biosimilar is as follows:
Phase 1: the applicant submits an application inquiry for box approval; box approval or disapproval is issued within 15 working days, if the box is opened, the following phases/steps have to be completed;
Phase 2: the applicant submits the pricing dossier within 30 working days of receiving box approval Pricing license issued within 60 W.D with 2 years validity period. During these 2 years:
- the applicant is allowed to purchase (in case of imported active substance) or produce (in case of locally manufactured active substance) specified amount of active substance required for manufacturing specified batch sizes for development;
- The applicant has to develop the biosimilar product, perform the quality and preclinical comparability studies along with preparation of clinical studies protocol. At the end, the results of quality and preclinical studies as well as the clinical studies protocol are submitted for evaluation.
Phase 3: An assessment of the submitted quality and preclinical comparability studies is performed by the regulatory authority and approval on clinical studies protocol is issued for the applicant to perform clinical studies with 2 years validity period. After completion of the clinical studies, the applicant completes the registration dossier to be submitted for validation and assessment.
Phase 4: An assessment of registration dossier is performed during this phase and the final assessment report is issued within 60 working days.
Phase 5: Reports collection for submission to Technical committee for drug control within 60 working days.
*After finishing the abovementioned registrations phases the next step will be the pricing, then reports collection & submission to technical committee for drug control and finally the last step will be the issuance of the license.
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 packaging of the biosimilar will be similar to the biological, the packaging of the products differs from the finished products and the local manufactured product packaging and wrapping materials must include the type and specifications of the components of the packaging & wrapping materials, in addition to the suppliers’ names.
There are no differences in the packaging requirements of the biosimilar drug and the biological drug.
5. What are the requirements for the choice of the reference comparator product?
The drug substance of the reference biological product and that of the biosimilar product must be similar, as the reference biological product should be authorized on the basis of complete dossier (full Quality, Preclinical and Clinical data).
6. Can the comparator product be sourced from another regulatory jurisdiction? If yes, what are the data needed to support this approach?
Yes, it is required that the reference biological product from another country be licensed and widely marketed in a reference country and with the same criteria that should be fulfilled on the reference product with the same standards in Egypt.
7. How are the prices of biosimilar medicines regulated? Is this any different to the requirements for the original Biologics drug?
No. there is no specific difference in the pricing requirements of both the biosimilar and the biological. The pricing regulatory framework in Egypt is regulated through Ministerial Decree No.314 of the year 1991, Decree No.373 of the year 2009 and Decree No. 499 of the year 2019.
The above-mentioned decrees clarify the pricing mechanism in Egypt, while the pricing requirements are regulated.
Pricing of the biosimilar medicines is regulated and follows the same rules and procedures of the biological and vaccines serums, which is promulgated in the Ministerial Decree No. 279 of the year 2009, after submitting the following documents:
- Pricing application form clearly mentioning the proposed price & pack, printing on the company paper & sealed with company seal;
- The approval on the query application;
- Payment receipt of the pricing services fees;
- Copy of free sales certificate in the country of origin notarized from the Egyptian Embassy abroad;
- List of cost, import price & price of the country of origin (notarized from the Egyptian Embassy abroad) (Original & Copy);
- Prices in other countries including Arab countries (Pricing form);
- Copy of the product’s original pack & insert.
8. What is the reimbursement policy for biosimilar medicine? Is this any different to the requirements for the original Biologics drug?
The reimbursement policy is similar to the method that is applied to the other drugs; the Ministry of Health and Population “MOHP” issues the reimbursement policies and regulations, which is followed by the MOHP’s facilities and the Health Insurance Organizations. The procurement department is mainly responsible for setting the reimbursement price and the tender drug list, which is published and distributed to all the MOHP facilities.
9. Does biosimilar competition impact the reimbursement policy of the originator reference products?
Biosimilars commands a great attention due to the significant cost saving and potentially wider use for the patents and achieve their medications demands for its affordability, accordingly, biosimilars have committed a competition with the original biological drugs due to its low prices.
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?
Up until now, there has been no legal framework regarding the prescription of the biosimilar specifically but the general rules of all drugs will be applied, physicians shall not recommend or prescribe medicines without applying appropriate examinations personally on the patient not according to an oral, written or visual data. For pharmacists they cannot dispense drugs without a medical prescription and the drugs shall be registered at the Ministry of Health, drugs that are not registered at the Ministry of Health shall not be distributed.
11. Is the system considering physician-led switching and/or pharmacy-level substitution (without involvement of the clinical decision maker)?
No, the pharmacists are not permitted to switch to patients from biologics to biosimilars, the biosimilar shall be prescribed by the physician, as the physician prescribes such medicine after examining and diagnosing the medical situation and also after being informed with the medical history of the patient and whether he is allergic to certain types of drugs.
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?
Yes, the requirements are different, as mainly, the biosimilars authorizations should cover two distinct but complementary aspects:
- The molecular characteristics and quality attributes (QA) of the target product profile should be comparable of those of the reference medicine product;
- The performance and consistency of the manufacturing process of the biosimilar should be achieved on its own.
- The quality of target product profile (QTPP) of a biosimilar should be based on data collected on the chosen reference medicinal product, including publicly available information and data obtained from extensive characterization of the reference medicinal product.
- The QTPP should be detailed at an early stage of development and form the basis for the development of the biosimilar end the manufacturing process. It is important to identify critical quality attributes that may impact the safety and efficiency of the product.
- In case of developing recombinant products, it is expected that the expression construct for a proposed biosimilar product will encode the same primary amino acid sequence as its reference product.
- The use of novel expression systems should be carefully considered, as they may introduce additional risk, such as atypical glycosylation pattern, higher variability or even a different impurity profile, as compared to the reference medicinal product.
- The expression of the active substance of the biosimilar product in the same host cell type of the reference product is expected to produce a product that will encode the same primary amino acid sequence.
- If the manufacturer used host cell type different from that of the reference biological product for development of a biosimilar product, more extensive comparability exercise should be employed top assure quality, efficiency and safety of the biosimilar product.
- However, demonstration of comparability for glycoproteins will be difficult because glycosylation patterns vary significantly between different host cell types.
- The following post- authorization shall be covered:
- Comparability key elements:
A comparability quality, pre-clinical and clinical data between the biosimilar product and the reference biological product using the product manufactured with the final manufacturing process, if changes are introduced to the active substances and/or finished product development, comparability assessment for the biosimilar product before and after change should be performed as per the ICH guidelines Q5E – comparability of biotechnological/ biological product subject to changes in their manufacturing process.
Collecting data from publicly available information and data from extensive analytical characterization for different batches of the reference product will enable the applicant to:
- Achieve the quality target product profile (QTPP) of the purpose biosimilar.
- Detect batch-to-batch variation within the batches of the same reference product.
- Specify the acceptance criteria for biosimilarity with justification.
Data from suitable number of batches, at least 3 pilot scale batches of the purposed biosimilar product at time of submission should be provided for proving similarity with the reference product.
Complete CMC should be submitted in CTD format according to ICH guidelines in addition to quality comparability exercise with the reference product.
Pre-clinical and clinical comparative studies with the same reference product used in the quality comparability exercise should be submitted. The extent of the preclinical and clinical data required depends mainly on the outcomes of the quality data.
Differences in quality pattern between the biosimilar and the reference product of unknown clinical relevance, particularly regarding safety should be addressed in additional studies pre-marketing.
Differences in quality pattern between the biosimilar and the reference product that is known to have potential impact on the clinical activity will influence the judgement whether to consider the product as the biosimilar or not.
Quality Aspects: level of comparability studies (drug substance and drug level product level)
- Product characterization studies for both the proposed biosimilar and the reference biological medicinal product should be performed using state of the art analytical methods.
- If the drug substance for the reference biological medicinal product is available, comparability exercise should be performed on both drug substance and drug product level but due to general unavailability of the drug substance of the reference biological product, comparability exercise is generally performed on the finished product.
- It is the responsibility of the applicant to demonstrate that the selected methods used in the comparability exercise would be able to detect slight difference in all aspects pertinent to the evaluation of the quality.
- Methods used in the characterization studies from an integral part of the quality data package and should be appropriately qualified for the purpose of the comparability. If the applicable standards and reference materials should be used for the method qualification and standardization.
A) Structural and confirmation characterization:
- A comprehensive set and combination of analytical methods are used; generally, characterization tests include but not limited to:
- Primary structures, such as amino acid sequence, N and C-terminal sequence
- Higher order structures, including secondary, tertiary, and quaternary structure (including aggregation)
- Enzymatic post-translational modification, such as glycosylation and phosphorylation.
- other potential variants such as protein deamidation.
- Intentional chemical modification such as pegylation sites and characteristics.
B) Specifications: Release of drug substance / drug product (DS / DP)
- Appropriate analytical test methods should be selected based on the nature of the protein being characterized and knowledge regarding the structure and heterogeneity of the reference and the proposed biosimilar product (ICH guidelines: Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products have to be consulted)
- Specifications for the proposed biosimilar product should be set based on the applicant’s own experimental results obtained for both the proposed biosimilar and the reference product, the specifications shall not be wider than the range of variability of the reference product unless justified.
- Each acceptance criterion should be established and justified based on data obtained from lots used for the demonstration of manufacturing consistency, data from stability studies, relevant development data and data obtained from the comparability exercise.
- Methods used for setting specifications may or may not be the same as analytical methods used for products characterizations and for establishing product comparability.
The comparability testing regarding the specifications includes:
- Physicochemical Properties: they include but are not limited to molecular weight/size, isoform pattern, extinction coefficient, electrophoretic patterns, liquid chromatographic patterns, spectroscopic profiles.
- Biological activity: Appropriate biological assays are required to characterize the activity and establish the product’s mechanism of action and clinical effects (in unit of the activity).
- Immunochemical properties: they include but are not limited to binding assays of the antibody to antigen, affinity, avidity and immune-reactivity (including cross reactivity).
- Purity and impurities:
-The purity and impurity profiles of the active substance and medicinal product should be compared both quantitatively by a combination of analytical procedures.
-Appropriate state of the art methods should be used to compare the product-related substances and impurities. This comparison should take into account specific degradation pathways of the biosimilar product and potentials post-translational modifications of the proteins.
-The age/shelf life of the reference medicinal products at the time of testing should be mentioned, and its potential effect on the quality profile should be discussed where appropriate.
-Comparison of the relevant quality attributes, tested at selected time of testing should be mentioned, and its potential effect on the quality profile should be discussed where appropriate.
-Comparison of the relevant quality attributes, tested at selected time points and storage conditions, could be used to further support the similarity of the degradation pathways of the reference medicinal product and of the biosimilar.
- Final Formulation:
-The formulation of the biosimilar does not need to be identical to that of the reference medicinal products. The applicant should take into account state-of-the-art technology and, regardless of the formulation selected, the suitability of the proposed formulation with regards to stability, compatibility (interaction with excipients, diluents and packaging materials), integrity, activity and strength of the active substance should be demonstrated.
-The acceptability of the type, nature, and extent of any differences between the proposed finished biosimilar product and the finished reference product should be evaluated.
-Differences in formulation between the proposed biosimilar product and the reference product are among the factors that may affect whether subsequent clinical studies may take a selective and targeted approach.
- Stability: Stability studies on both drug substance and drug product following “ICH guidelines “Quality of biotechnology products: stability testing of biotechnological/biological product QC5” should be consulted. At time of submission, stability data for 6 months as minimum on at least 3 pilot scale batches into the long-term stability program after approval. The quality of the pilot batches should be representative of the quality of the materials used in the pre-clinical and clinical studies and of the quality of the material made at production scale. Side by side accelerated and stressed studies comparing the biosimilar product to the reference product will be value in determining the similarity of the products showing comparable degradation profiles.
Pre-Clinical Aspects: The design of an appropriate pre-clinical study program requires a clear understanding of the product characteristics outcomes from the quality comparability data and depends on the product class. Generally, the spectrum of studies required to establish safety & efficacy of the biosimilar product may vary considerably & should be defined on a case-by-case basis. General considerations of the preclinical studies:
- pre-clinical studies should be comparative in nature between the proposed biosimilar and the reference product;
- More than one aspects of comparability can be addressed in one study depending on the study design (which considers the objective(s), Evaluation criteria, system used …)
- performing preclinical studies should take into consideration
The pre-clinical studies required for evaluating a biosimilar product are:
- In Vitro studies: (Pharmacodynamic Studies):
- In Vitro studies: (Pharmacodynamic/Toxicological/Immunogenicity Studies)
Which are performed to address toxicity – pharmacodynamics – local tolerance – Immunogenicity)
Clinical Aspects: The scope and extent of the clinical studies will depend on the outcomes of the comparability quality and preclinical data.
In addition to the clinical study which addresses the following aspect: PK parameters, PD markers, safety, efficiency, immunogenicity)
A confirmatory efficacy study is required to demonstrate biosimilarity, this study can be waived if all the following conditions are met:
- PK of reference product are well characterized and the relationship between dose/response and response/efficacy of the reference product as “concentration – response” curve is known (for example from literature).
- Structural and functional comparability of biosimilar and reference can be characterized to a high degree of confidence by physicochemical and in vitro techniques.
- The biosimilar product is comparable to the reference product in all preclinical and evaluations conducted.
- PK/PD study has demonstrated comparability and has preferentially been done in an inpatient setting with safety measurement (including immunogenicity) for adequate period justified by the applicant and efficacy measurements.
- A comprehensive post marketing risk management plan has been presented that will gather additional safety data with a specific emphasis on gathering immunogenicity data.
- At least one PD marker is accepted as a surrogate marker for efficacy, and the relationship between dose/exposure to the product and this surrogate marker is well known.
Batches: Clinical studies should be conducted with the final formulation. Generally, it is required to generate the clinical data for comparability study with the biosimilar product as produced with the final manufacturing process and therefore representing the quality profile of the batches to be commercialized. If there was a manufacturing change during development, comparability should be evaluated in line with ICH Q5E Guideline, as necessary.
Extrapolation of indication could be possible if the following conditions are met:
- A sensitive population criterion that is able to detect potential differences between biosimilar and reference product is used.
- The clinically relevant mechanism of action and or involved receptor(s) are the same
- Safety and immunogenicity of the biosimilar product have been investigated in the patient population that carries the highest risk of an immune response and immune-related adverse event, thus sufficiently characterized and there are no unique/additional safety issues expected for the extrapolated indication(s)
- The efficacy trial used a non-inferiority study design and demonstrated acceptable safety and efficacy of the biosimilar compared to the reference product, the applicant should provide convincing arguments that this finding can be applied to the extrapolated indications.
If the above-mentioned conditions for extrapolation of the efficacy and safety data of the biosimilar to other indication(s) of the reference are not fulfilled, the applicant will need to submit its own clinical data to support the desired indication(s).
Pharmacovigilance Plan: Product pharmacovigilance plan according to the EPVC guidelines should be submitted, this plan should include protocol for post marketing immunogenicity study at the time of submission of the marketing authorization application.
Risk Management Plan: RMP should be presented to the EPVC and should include post marketing immunogenicity study at the time of submission of the market authorization application.
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?
No, there are no specific requirements that differ from any other labelling requirements of pharmaceuticals, the labelling requirements are regulated under Ministry of Health Decree 425 of the year 2015 and the Guidelines for Outer Label of Pharmaceutical Products issued by CAPA, the labelling requirements are as follows:
The outer label must contain the following information:
- Trade name as approved by CAPA;
- Active ingredients under the trade name and on the side of the package;
- Pharmaceutical form under the active ingredients;
- Number of units per pack;
- Route of administration;
- Any other ingredients if they are not mentioned in the leaflet;
- Storage conditions;
- Special precautions;
- Information on the manufacturer (name, address, city, country, phone, fax, website) and license holder (logo or trade mark);
- Barcode of the product;
- Batch number;
- Production and expiry dates;
- The dosage form or the product if it relates to a specific group (infant, children, adults, men, and women);
- The approved price for each unit and the whole package;
- All drugs must state “keep out of the reach of children”; and
- Other contents in the package must be mentioned on the outer label (if any, for example, measuring cup, applicator, dropper, syringe, calibrating dropper, and so on).
All information on the outer label must be written in both Arabic and English. Further, the design and color of the outer label must differ from that of competitor products.
In case of dietary supplements, a ribbon (15% of the package size) must encircle the package. In this ribbon, the words “Dietary Supplement” must be written, in both English and Arabic.
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).
The regulatory framework of the Pharmaceutical’s IP is regulated through the Intellectual Property Rights Law No. 82 of the year 2003 and its Executive Regulations, as per this law patents can be granted for an amendments, modifications, or addition to an invention already granted a patent, provided that the conditions of novelty, innovation and industrial applicability are met. The patent is valid for 20 years from the application filing date, and an annual maintenance fees shall be paid until the expiry date of the patent protection.
Under the aforementioned law, there is a patent infringement in the following cases:
- counterfeits with the aim of commercial circulation;
- unlawfully placing on products, adverts, trademarks, packaging materials or other materials information leading to the belief that the party has registered an invention patent or utility model patent.
In the pharmaceutical sector, Patent registration is lengthy (about three years), some pharmaceutical companies do not wait for the patient registration and they start selling their products, some others register their products with the MOH before even applying for patent registration.
The IPR Law stipulated that the patent infringement is a criminal offence punishable by a fine of at least EGP 20,000 up to EGP 100.000. In case of a recurring offence, imprisonment of no more than two years and a fine of at least EGP 40,000 up to EGP 200,000 will be applied.
In all cases, the court can order confiscation of the counterfeit products, the court judgment in case of patent infringement is published through internet and newspapers.
The owner can also claim damages or seizure of infringing products through a claim in the civil court.
The economic court has jurisdiction over IP matters. Further, Article 33 of the abovementioned Law stipulated that the owner could request from a court a precautionary measure against products or goods suspected to infringe a patent, to preserve the patent owner’s right. In that case, the court can issue a preliminary injunction before the main proceedings. The main preliminary injunction will expire if the main proceedings are not brought within eight days from the date of the injunction.
Competition is regulated under Law No. 3 of 2005 on the Protection of Competition and the Prohibition of Monopolistic Practices and its executive regulations (Competition Law). Article (5) provides that the Competition Law also applies to acts committed abroad if they result in the prevention, restriction or harm of/to freedom of competition in Egypt, and are offences under the Competition Law.
The Competition Authority enforces the Competition Law. It receives mergers and acquisitions notifications and reports of violations. Its board of directors can refer a case to prosecution on a written request of the chair if it obtains majority board approval. The Competition Authority can also opt for an out-of-court settlement.
Abuse of a dominant position is prohibited. The Competition Law considers an entity to be in a dominant market position if it holds over 25% of the relevant market share, can change the prices or volume of products offered in that market and competing parties cannot prevent this.
The Competition Law prohibits persons from entering into agreements that limit competition with their suppliers or clients. Competing persons in a relevant market cannot carry out price-fixing, market allocation, bid-rigging and output restrictions. However, there is an exception for horizontal agreements approved by the Competition Authority if the restrictive effect on competition is outweighed by the benefit to consumers.
The Competition Authority is very active. In 2016, it reviewed 28 complaints of anti-competitive practice, and issued a decision in 22 of them. However, there are not many cases concerning pharmaceuticals.
In 2015, the Competition Authority referred four drug distribution companies to prosecution for violating Article 6(a) and (d) of the Competition Law, by coordinating their marketing and selling terms for small and medium pharmacies and reducing the credit terms and cash discounts offered. In 2018, they were fined EGP500 million by the Egyptian courts. It is considered the largest fine in Egypt for competition violations.
In 2016, the Competition Authority challenged the Ministry of Health’s regulations on pricing and registration of drugs under Ministerial Decree No. 425 of the year 2016. The Competition Authority argued that this decree creates restrictions inhibiting the entry of new investors into the market, leading to a monopoly of big market player entities through their acquisition of other companies. The Competition Authority also challenged Decree No. 499 of 2012, arguing that the pricing mechanism breaches the principles of free competition and equal opportunities. These challenges did not lead to any changes in these laws.
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?
No, up until now, there have been no proposals of applying any significant change to the regulation of biosimilars in Egypt.