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Revista Brasileira de Epidemiologia

Print version ISSN 1415-790X

Rev. bras. epidemiol. vol.15 no.4 São Paulo Dec. 2012 



Relevant issues to biossimilars licensing



Beatriz Serrapio PeresI; Gabriela PadilhaII; Cristiane QuentalIII

INational Health Surveillance Agency (ANVISA) - Coordination of Intellectual Property
IIOswaldo Cruz Foundation / Health Innovation and Manufacturing Vice-Presidency
IIIOswaldo Cruz Foundation / Sérgio Arouca National School of Public Health

Correspondence to




When the patent of a drug expires, low cost generics may be introduced in market. Trial results that demonstrate the safety and efficacy of the reference product can be extrapolated to the generic, simplifying the approval process. This paradigm cannot be applied to biopharmaceutical products, large molecules difficult to be characterized. Minor changes in the production process can influence the biological and clinical properties of the product and result in differences in efficacy and safety profiles. It is not possible to demonstrate the identical nature of biopharmaceuticals arising from different manufacturing sources, so they cannot be approved as simple generics and need specific regulation. A bibliographical survey of the main issues involved in the approval of similar versions of biopharmaceuticals was performed as well as a comparative analysis of the regulatory situation in the largests pharmaceutical markets - U.S. and European Union - based on legislation, draft laws, guidelines and technical references issued by their regulatory agencies - FDA (Food and Drug Administration) and EMEA (European Medicines Agency), respectively, in order enlight the discussion now taking place in Brazil. Based on the laws and guidelines studied, it is concluded that, although Brazil, Europe and the United States are at different stages of setting their regulatory framework for biossimilars, it is possible to identify some similarities in approach, such as the need for different treatment for each product class (or a case by case focus) and a step by step comparison exercise, the results of which will define the amount of data and non-clinical and clinical studies required. However, issues such as interchangeability and automatic substitution of biossimilars for reference products are not yet clearly defined. From the sanitary point of view, Europe has a more conservative posture, while the U.S. and Brazil seem to be building a more flexible framework. Besides the health issues, however, we highlight the economic issues, of great importance in Europe and U.S. legislation, and not addressed in the Brazilian regulation - which can bring insecurity to producers interested in this market.

Keywords: Drug approval. Similar drugs. Biological products/therapeutic use.




When the patent of an innovator drug expires, as in the case of biopharmochemical drugs, generic drugs may be introduced into the market, assuring patients access to safe, effective and lower cost products. However, drugs developed through modern biotechnical techniques, known as biopharmaceutical drugs, are considered more complex than biopharmochemical drugs, in terms of structure, manufacturing and drug action. Biopharmaceuticals are more difficult to be adequately characterized, considering current analytical techniques. The standard approach applied to generic drugs is scientifically inadequate to the development of biosimilar products and, in general, additional non-clinical and clinical data are required1.

Important biopharmaceutical drugs gained patent protection during the 1980's; therefore they will soon be unprotected (e.g. insulin, human growth hormone and erythropoietin). Launching replicas of these innovator products would introduce competitiveness into the market and allow price reduction. In general, biopharmaceuticals cost more per patient than conventional drugs, limiting access to important treatments (diabetes, cancer, chronic renal failure, chronic hepatitis). In Brazil, expiration of the patent term of these products represents an opportunity for domestic manufacturing of these drugs.

This issue becomes more relevant as these products are not only an essential part of the drugs available today, representing 6% of the worldwide pharmaceutical drugs marketed, but mainly because one third of these are biotechnological products2 indicating exponential growth of this segment.

With no legal boundaries or clear guidelines for biosimilar drug approval, however, patent expiration may be accompanied by the introduction of low price competitor biopharmaceutical drugs in the market. Moreover, the absence of clear guidelines leading to a product comparison in relation to reference products may result in the approval of products without sufficient proof of safety and efficacy.

In the present study, a revision of the main issues involved in the approval of similar versions of biopharmaceutical drugs in the literature, and a comparative analysis of the regulatory situation in the major markets - U.S. and European Union - based on legislation, draft bills, guidelines and technical references issued by their regulatory agencies - FDA (Food and Drug Administration) and EMEA (European Medicines Agency), respectively, was performed. Both experiences will certainly influence regulatory procedures which other countries may adopt as well as impact on the future global strategy for biosimilar products. The main aspects of the discussion and their relevance to Brazilian regulations are identified. Results are presented as follows.


Main Issues Involved in the Licensing and Clinical Use of Biosimilars

The term "biosimilar" has its origin in the difficulty to compare two versions of the same biopharmaceutical drug whose properties are deeply related to each of their manufacturing processes. Minor changes to the process may lead to contamination, three-dimensional structure changes of protein and changes in the glycosylation profile which affect both biopharmaceutical drug potency and immunogenicity3.

Given specific manufacturing process information as well as validation and full characterization data of therapeutic proteins are generally a company's intellectual property, it will probably be difficult for another manufacturer to reproduce a biopharmaceutical drug similar enough to the original innovator product, based only on the patent or in published data4.

Since proteins are complex molecules, it would be difficult to demonstrate the identity between two biological products from different manufacturers or sources5. In addition, current analytical techniques cannot detect or predict all clinical and biological properties of proteins, so differences among biopharmaceutical drugs can easily remain hidden3.

Demonstration of Similarity

Despite the predominant view that comparative studies are essential, there is no consensus as to what extent they would be necessary. In some cases the necessary effort to perform a comparative study between a biosimilar and a reference product may be greater than licensing the potential biosimilar as an independent product1.

The amount of clinical data depends on numerous factors including drug purpose and mechanism of action. Smaller and non-glycosylated proteins (such as insulin, somatropin) are easier to be completely characterized, whereas highly glycosylated proteins (such as epoetin) or very large proteins (such as monoclonal antibodies and blood factors) cannot generally be completely characterized6.

Another important issue is the choice of the reference product. In general, countries expect the reference product to be a locally registered drug. However, one must consider the possibility of a company wishing to register a biosimilar in a country in which the reference product is not licensed, increasing the opportunity of access to innovator biological drugs and making it easier to introduce biosimilars in some markets1.

Safety in Clinical Use

The most important aspect regarding the safety of biosimilars is immunogenicity5. All biopharmaceutical drugs demonstrate ability to trigger an immune reaction, as they are polypeptides or proteins. This reaction may be mild but there is potential to cause allergies and anaphylaxis. Moreover, the development of antibodies can neutralize the therapeutic protein, causing loss or reduction in efficacy. Immunogenicity may be influenced by factors related to the drug, such as the manufacturing process and its formulation, and by factors related to patient, disease and treatment, such as route of administration7.

Immunogenicity cannot be predicted in preclinical testing and in some cases it is only detectable after long term treatment5. A great number of cases of PRCA (Pure Red Cell Aplasia) were caused by the development of neutralizing antibodies against recombinant erythropoietin, detected more than 10 years after the introduction of erythropoietin for the treatment of renal anemia. The likely cause was a small change in the formulation. Furthermore, the replacement of the stabilizer, human serum albumin, for polysorbate 80 may have interacted with the rubber existing in syringes. Modification of syringe material and changing the route of administration led to an almost complete disappearance of PRCA8. The only way to measure the immune response of a drug is via clinical trials and it is highly important to have a pharmaceutical surveillance plan for each biological product being introduced into the market.

Automatic Replacement, Naming and Labeling of Biosimilars

Automatic replacement allows dispensing generic drugs instead of a prescribed innovator drug without the knowledge or consent of the doctor. In the case of conventional generic drugs, the risk of this replacement is generally low8.

If automatic replacement is allowed, patients may receive multiple biopharmaceutical drugs during therapy, which may impair the collection of pharmaceutical surveillance data. Therefore, for safety monitoring, it is essential to know exactly which biopharmaceutical was given to each patient5.

According to Nowick8, as biotechnological medicines are not identical the original products and biosimilar labels must be different. In the case of biosimilars the reference product must be determined.

It is important to highlight that some European countries such as France, Germany and Spain have prohibited automatic substitution of reference biological medicines by biosimilar drugs9.

Clinical Data Extrapolation

Extrapolation refers to the approval of a drug for indications for which it has not been evaluated in clinical trials. For example, the approval of the biosimilar growth hormone Omnitrope in Europe included comparability studies with the reference product, Genotropin, conducted only in children with growth disorders. However, the labeling of Omnitrope includes the indication for use in adults. The reasons for data extrapolation between the innovator product and a biosimilar include: long clinical history of safe use of growth hormone; wide therapeutic window for the drug; rare reports of neutralizing antibodies; the ability to characterize the structure and biological activity of growth hormones by physical-chemical and biological methods; and, the variety of tests available to characterize the active substance5.


European Union and U.S. Position on Licensing of Biosimilars

The regulatory approach of issues involving licensing and use of biosimilars is still being defined in many countries, including Brazil. The path followed in major markets - U.S. and European Union - will undoubtedly influence regulatory procedures that other countries will adopt and will also impact the future global strategy for biosimilar drugs. The following topics will present an overview of the legal and regulatory status in these countries. Chart 1 shows the position of the U.S., the European Union (and Brazil) in relation to the main issues involving the use of biosimilars based on approved legislation in each country/region and guidelines, directions and edited guides published by drug regulating authorities.

The European Union Approach

The European Union has specific legislation which regulates biosimilar product licensing. On this legal basis it has established a regulatory framework which includes guidelines with general directions and additional guidelines, specific to each product class.

The European Community Directives10-12 provide legal basis to determine that if the required information for similar drugs does not prove the similarity of two biological drug products, additional data must be provided, such as the toxicological and clinical profiles, determined case-by-case by the competent authority, taking into account the specific characteristics of each drug. If the reference drug has more than one indication the safety and efficacy of a biosimilar drug should be demonstrated separately for each of the claimed indications.

The period of exclusivity for the reference product determines that biosimilar drug approval requests can only be filed after the period of data exclusivity, which is of 8 years. Authorized biosimilars can only be introduced in the market after the period of market exclusivity of 10 years. Furthermore, when a request is made for a new indication of a well-established substance, a one-year period of data exclusivity will be granted provided pre-clinical or clinical trials relating to new indications have been conducted. The period of market protection can be extended by one year in case of new therapeutic indications, provided the new application represents significant clinical benefits and has been approved during the first 8 years of the initial marketing authorization.

On this legal basis, the EMEA Committee for Medicinal Products for Human Use - CHMP issued a regulatory framework consisting of a general guideline13, which brings the concept of similar biological medicine and the adopted principles, in addition to a registration request form; quality guidelines14; and clinical and pre-clinical study guidelines15, in that the latter two refer to specific appendixes for different product classes such as somatropin, insulin, epoetin and G-CSF.

In 2011, documents ("concept papers") were published proposing the review of the three above-mentioned guidelines which form the backbone of the EMEA regulations for licensing of biosimilar drugs. These documents emphasize the need to review these guidelines in relation to the elapsed time since their approval and the experience gained by the Agency in approving various biosimilar drugs16-19.

There are specific guidelines for recombinant human insulin, somatropin, G-CSF, recombinant interferon alpha, heparin, recombinant erythropoietin. There are also guidelines for recombinant follicle stimulating hormone, monoclonal antibodies and IFN-beta, not yet concluded. These documents require clinical and non-clinical data describing the size of trials needed and the best indication to demonstrate equivalence for each product compared with a reference product16, 20.

Besides these three main guidelines, the document "Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins"21 is relevant because it considers the immunogenicity assessment addressing factors that may lead to immunogenicity, from development, planning and interpretation of clinical and non-clinical trials to evaluate the immunogenicity potential and its comparability with other products, to the implementation of a risk management plan.

EMEA Guidelines indicate a comparability exercise which is a step-by-step comparison in terms of quality, safety and efficacy in order to demonstrate that a biosimilar drug and the reference product have similar profiles in these aspects.

U.S. Approach on Biosimilars

In the U.S., the legal basis for biosimilar drug licensing is more recent and the result of intense debate in the U.S. Congress, a forum for competing bills which clearly favors the interests of potential manufacturers of biosimilar drugs and projects more favorable to the pioneering drug industry - the former more and the latter less flexible as to the requirements for approval of similar products, such as the legal requirement for clinical trials, exclusivity periods, among others22-24. The Biologics Price Competition and Innovation Act (BPCI Act) enacted as part of the Patient Protection and Affordable Care Act (PPACA), signed into law by President Obama in March 2010, which underlies the licensing of biosimilar products in the U.S., adopted an intermediate stand between the two positions 25. Few clinical trials are required by law, small variations are accepted, the approval is concentrated mostly in the hands of the FDA, but the period of exclusivity for innovators is long (Table 1).

The BPCI Act amends section 351 of the Public Health Service Act, determining the requirements for approval through an abbreviated pathway for biological products which are highly similar (biosimilars) or interchangeable with a biological product previously licensed by FDA. It also determines that the FDA will license a product as a biosimilar if it considers that the information provided is sufficient to demonstrate biosimilarity and that the manufacturing facilities subject to licensing application are inspected.

The FDA describes a biosimilar product as a biological product highly similar to an already-approved biological product, despite minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the biosimilar product approved in terms of safety, purity and potency. The Agency understands that there are no biological generic products and additional data from clinical safety and efficacy studies required26.

It is important to highlight that the position adopted by the FDA was to wait for the definition of a legal basis to publish specific guidelines for biosimilar products4. Before approval of the BPCI Act, some less complex therapeutic proteins were approved as biosimilars of products registered under the Food, Drug, and Cosmetic Act (FD&C Act), based on a case-by-case analysis, such as human growth hormone and somatotropin. However, the knowledge and technology available would allow the approval of more complex products through an abbreviated pathway27.

After the approval of the BPCI Act, the FDA held a public hearing and set a public document which addresses the specific issues and challenges associated with the implementing of the legislation on biosimilars28. On February 9, 2012, the FDA issued three draft guidelines for discussion and commentaries 29,30,31.

The Scientific Considerations in Demonstrating Biosimilarity to a Reference Product draft guideline points to the factors which will be considered by FDA in the evaluation of biosimilarity, such as product complexity, formulation and stability, and biochemical characterization. The approach will be based on risk considering the totality of the evidence or data, and referring to certain product characteristics, such as the mechanism of action, product structure-function relationships, manufacturing process, and clinical experience with the reference product. The amount of data and information needed will be determined case-by-case.

This draft guideline also stresses that despite advances in the analytical sciences that allowed extensive characterization of some protein products, they may not be able to detect all relevant structural and functional differences between two proteins. Therefore analytical, animal and clinical study data are required for the demonstration of biosimilarity unless the FDA determines that an element is unnecessary.

The Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product draft guideline emphasizes the importance of extensive analytical, physical-chemical and biological characterization. Any differences between the proposed biosimilar product and the reference product and its potential effects on safety and potency should be described and discussed.

The Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 draft guideline provides questions and answers grouped into three main categories on the themes of: Biosimilarity or Interchangeability, Provisions Related to the Requirement to Submit a BLA for Biological Product and Exclusivity.


Brazil´s Position on Licensing of Biosimilars

In Brazil, regulations on biological and biotechnological products were subject of discussion in different forums with significant involvement of entrepreneurs, class representatives, academics, government laboratories and ANVISA, with a view to draft proposals for the review of the Brazilian regulation.

The National Health Surveillance Agency by Public Consultation 49/10, issued on May 25, 2010, presented a Resolution proposal on the registration of biological products. The final text of Resolution 55/201032 was finally published on December 17, 2010.

Brazilian regulation is much more general and simplified than the American and European cases studied. With respect to safety and efficacy it is careful to require, in addition to pivotal clinical trials, pharmaceutical surveillance and immunogenicity studies, but does not go beyond what is currently being done in the European Union, in aspects such as the difficulty to prove the identity of these products in relation to the reference products; the extent and nature of clinical and preclinical data required, taking into account the characteristics of the product, the ability to characterize it with current analytical techniques (which depends on its structural complexity), dosing regimen, target population etc.; establishing an appropriate approach for evaluation of immunogenicity, including comparability test validation; naming, labeling and interchangeability issues.

Resolution 55/2010 determines that biological products can be registered through a development pathway by similarity. It is defined as the "regulatory pathway that can be used for a biological product to obtain registration with the regulatory authority, in which similarity was determined in terms of quality, safety and efficacy between the product developed and to be compared, and the biosimilar reference product". The biosimilar reference product must be an Anvisa-registered product with a full registration-based dossier*, where the same reference product must be used in all stages.

Under Resolution 55/2010 the application for registration of a biological product by a development pathway by similarity should provide information such as: description of the analytical techniques used to detect potential differences between the biological product and the biosimilar reference product, biological and physical-chemical characterization data related to the biological product quality attributes; information on the expression system used to manufacture the biological product and the biosimilar reference product; molecule similarity between the biological product and biosimilar reference product; detailed description of the similarity assessment stages; accelerated and stress comparative stability studies; description of the observed differences in purity and impurity profile between the biological product and biosimilar reference product; evaluation of the contaminants and impurities identified in the biological product, discussing the potential impact on quality, safety and efficacy; analytical characterization of the biological and biosimilar reference product; results of comparative biological tests needed to determine the degree of comparability; and conclusive report with demonstration of comparability, containing sufficient information to predict whether the detected differences in the quality attributes result in adverse impacts on the safety and efficacy of the biological product.

In addition, the applicant company should present non-comparative clinical studies, designed to detect significant differences between the biological product and biosimilar reference product. Relevant pharmacodynamic studies for the intended therapeutic indications and studies of cumulative toxicity (repeated dose) are required. In reference to clinical studies, pharmacokinetic and pharmacodynamic studies are mandatory; along with a pivotal study of clinical safety and efficacy.

In 2011, ANVISA issued the "Guideline for Conducting Comparability Exercise for Biological Products Licensing"33, with directions to perform the comparability exercise for biological product registration by the development pathway of comparability according to RDC55/2010. As in the guidelines proposed by the FDA, the guideline issued by ANVISA proposes a gradual approach, in stages, starting with the characterization and assessment of quality attributes of the product, followed by clinical and nonclinical studies. The characterization and comparison at a quality level would be the basis for a possible reduction of studies in the clinical and nonclinical development stage. If differences are found between the biological product and the biosimilar reference product the reasons should be investigated and justified, which may lead to additional data requirement. The amount of clinical and nonclinical data required will depend on the product; on the degree of characterization possibly undertaken with modern analytical methods; on the differences observed in relation to the clinical experience reference product and the product class. The guideline stresses the need for a case-by-case analysis for each product class.

Table 1 compares the Brazilian position in relation to that of the U.S. and the European Union.


Final Considerations: Implications for Regulating Biosimilar Drug Licensing in Brazil

Most biopharmaceutical drugs are complex products with high added value, and patent term expiry for innovator products represent the opportunity for replica of these products, increasing the population's access to new treatment possibilities. If on one hand there is all this potential, on the other hand the regulatory barriers for biosimilars are still significant. The main aspect is the difficulty in predicting the safety and efficacy of these products.

Case analysis clearly demonstrates that a regulatory procedure for biosimilars will be different from that existing for generic drugs and that the tendency is to seek specific guidelines for product categories, and it is the regulatory authority's competence to assess the extent of required data as well as the appropriateness of a study, deciding on interchangeability.

Although Brazil, Europe and the United States are each at a distinct stage of definition and establishment of their regulatory framework for biosimilar drugs, similarities in the approach can be identified: the need for differential treatment for each product class, with specific guidelines (as in Europe) or a case-by-case focus (as indicated in the proposed American Guidelines and Anvisa Guidelines); the indication of the importance of full and extensive analytical studies, as the first stage of a step-by-step approach when it identifies potential differences between the biosimilar candidate and the reference product, which will dictate the data and the extent of the clinical and nonclinical studies of later stages. From a health point of view, Europe has a more conservative position, whereas the U.S. and Brazil seem to be building a more flexible framework.

However, based on the European and American legislation and guideline analysis we can state that the discussion goes beyond the issue of safety and efficacy, reaching the economic aspects of investment in biosimilar drug manufacturing. In this sense, one of the most controversial aspects is the existence of periods for data and market exclusivity, justified by the need to promote innovation. It is possible to anticipate that this issue is still the subject of intense debate, which has not yet been considered in Brazilian regulations and which can bring insecurity to manufacturers interested in this market.

The great challenge for regulatory agencies will be to deal with the risks and benefits inherent to biosimilar drugs, while not introducing excessive barriers to development and approval, in order to promote domestic production and greater access to safe and effective products for the Brazilian population.



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Correspondence to:
Cristiane Quental
Rua Leopoldo Bulhões, 1480 s. 703, Rio de Janeiro, RJ
CEP 21041-210.

Received: 02/09/11
Final version: 29/05/12
Approved: 10/07/12



* The Complete Dossier "is the total set of documents submitted to ANVISA for demonstrating the attributes of quality, safety and efficacy of a biological product. This file consists of the complete characterization of the product and detailed description of the manufacturing process, demonstrating consistency in drug manufacturing, further to substantial safety and efficacy clinical evidence demonstrated by means of clinical and non-clinical phase I, II and III studies. "(Resolution 55/10 of the National Health Surveillance Agency dated of December 17, 2010).

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