Availability of Biosimilar Pathways and Data Exclusivity in Asian, Latin American and Eastern European Countries

Biologics have become a big business. In fact, it is predicted that in twenty years, biologics will replace 70% of the global chemical (small molecule) drugs. Moreover, the global biosimilar market is expected to reach $3.7 billion dollars by 2015. The emerging markets of Asia, Latin America and Eastern Europe are particularly attractive for this growth. Some of the reasons is that these countries: (1) have a growing middle class; (2) are increasing their expenditures on healthcare; and (3) have a generic driven pharmaceutical markets.

In view of these tremendous market opportunities, we at the BRIC Wall thought it would be helpful to examine the availability of biosimilar pathways and data exclusivity for reference (innovator) biological products in several Asian, Latin American and Eastern European countries. The results of our efforts are shown in the below table.

Country

Biosimilar (Abbreviated) Pathway in Place

Data Exclusivity for a Reference Biological Biological Product

China

No

No

South Korea

Yes

No

Malaysia

Yes

Yes1

Thailand

No

No

Taiwan

Yes

Yes – up to 5 years

Singapore

Yes

Yes – up to 5 years

Philippines

No

No

Vietnam

Yes

Yes2

Indonesia

No

No3

Russia

No

No

India

Yes

No

Turkey

Yes

Yes – up to  6 years4

Brazil

Yes

No

Argentina

Yes

No

Chile

Yes

Yes – up to 5 years

Venezuela

Yes

No

Peru

Yes

Yes – up to 5 years

Ecuador

No

No

Columbia

No

No

Mexico

Yes

No

1Malaysia has guidelines on data exclusivity; however, these guidelines are not specifically directed to a reference biological product for biosimilars. However, we believe that the definition of “a new drug product containing a new chemical entity” for which data exclusivity is available would cover any such reference biological product provided that the product meets the requirements. “A new drug product containing a new chemical entity” refers to a product that contains an active moiety that has not been registered in accordance with the provisions of the Control of Drugs and Cosmetics Regulations 1984. An “active moiety” is defined as a “molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.” The duration of data exclusivity is (1) up to five years for a new drug product containing a new chemical entity {which is calculated from the date the product is first registered or granted marketing authorization AND granted data exclusivity/test data protection in the country of origin or in any country recognized and deemed appropriate by the Director of the Drug Control Authority (“Director”)}; or (2) up to three years for a second indication (which is calculated from the date the second indication is first approved AND granted data exclusivity/test data protection in the country of origin or in any country recognized and deemed appropriate by the Director).

2Vietnam has provisions for data exclusivity generally; however, it does not make specific reference to a reference biological product used in comparability studies with a biosimilar product. The Ministry of Health (MoH) issued a circular dated March 1, 2010 providing guidelines for data exclusivity in Vietnam. The data exclusivity provisions apply to the registration of finished drugs that contain a new active ingredient. Because the definition of “drugs” includes biological medical products, we believe that this definition would also include reference biological products. The MoH is required to keep the data confidential for a period of five years from the date on which a pharmaceutical company is granted a license for marketing approval. The duration is shorter in those cases where the exclusive data does not meet the requirements for trade secret protection.

3Indonesia does not have any specific regulations that provide for data exclusivity. However, the protection of data and experiments relating to a drug is automatically provided by the Government (namely, the Ministry of Health) once a drug is registered. Specifically, Article 14(3) of Health Ministry Regulation of R.I. no. 10101 MENKES/PER/XI/2008 provides that a “registration document is a confidential document which can only be used for evaluation by the relevant officer.”

4In many countries, the periods of patent exclusivity and regulatory data exclusivity are completely independent and separate from each another. However, in Turkey, this is not the case. In Turkey, the period of data exclusivity is tied to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. Specifically, the data exclusivity period for a biological reference product is six years from the date of first registration of the product in the European Customs Union {which comprises the member states of the European Union (such as Great Britain, Germany, France, Italy, etc.) as well as some other non-European Union countries (such as Turkey)}. However, this six year data exclusivity period is limited to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. For more information, see our previous post on “Understanding Biologics and Biosimilars in Turkey”.

The BRIC Wall would like to thank the below firms that provided the information that is included in the above table.

Argentina, Chile, Columbia, Ecuador, Peru and Venezuela: Clarke, Modet & Co.

Brazil: Dannemann Siemsen

India: Chadha & Chadha

Indonesia, Malaysia, Philippines, Singapore, Thailand, Vietnam: Spruson & Ferguson

Mexico: Olivares & CIA, S.C

Turkey: Deris Patents & Trademarks Agency A.S.

Republic of Korea: Central Intellectual Property & Law

Russia: Gowlings

Taiwan: Lee & Li

Patentees Can Continue Patent Infringement Lawsuits in Russia Even if a Patent is Found to Be Partially Invalid

Russia has a bifurcated system for handling patent infringement lawsuits and patent revocation proceedings. The venue for patent infringement proceedings is the Russian Court system and the venue for revocation proceedings is the Russian Patent Office (ROSPATENT), specifically, the Chamber for Patent Disputes (Chamber). If as a result of a revocation proceeding a patent is deemed to be partially invalid, the patent is nullified in its entirety and an amended patent having a new patent number and containing the claims adjudged to be valid is issued within a few months.

Until recently, if during a patent infringement proceeding an asserted patent was found to be partially invalid by the Chamber, the infringement action was dismissed in full. The reasoning used by courts to dismiss such actions was that the asserted patent (with its specific patent number) no longer existed and there could be no infringement until the amended patent was granted. In such situations, the patentee’s only recourse was to wait until the amended patent issued, and file a new patent infringement action. Unfortunately, as a result, the patentee would have to begin its case again from the very beginning even if the defendant’s product infringed the claims of the amended patent.   

In Bayer vs. Gedeon Richter et al. (No. А40-90149/11-51-791), the Supreme Arbitration Court (SAC) issued a decision changing the approach Russian courts will have to use when considering patent infringement lawsuits in instances where an asserted patent is subject to partial invalidation by the Chamber.  

The case involved a contraceptive developed by Bayer comprising a combination of the active ingredients ethinylestradiol and drospirenon. This concentrative has been sold in Russia under the trade names Yarina and Yaz. Bayer filed and received Russian Patent No. 2269342 which claims a pharmaceutical composition comprising a combination of these active ingredients. The patent expires in 2020. 

Gedeon Richter (Gedeon), a Hungarian generic drug manufacturer, received marketing approval and began to sell (in Russia) a generic copy of Bayer’s branded Yarina and Yaz products under the trade name Midiana. In response, Bayer filed a patent infringement action in August 2011 against Gedeon and several other companies involved in the supply of Midiana. 

In response to Bayer’s filing, Gedeon filed a revocation action against Russian Patent No. 2269342 in the Chamber. The revocation action proceeded very quickly, and on December 13, 2011, the Chamber held that Bayer’s patent was partially invalid. Because the patent infringement proceeding was still pending before the court of first instance (namely, the Moscow city Arbitration Court), the court quickly dismissed the infringement action on February 21, 2012, holding that Bayer did not have an enforceable patent at the time of the proceeding. This decision was upheld by the second and third instance courts (namely, the Ninth Arbitrazh Appeal Court and the Federal Arbitrazh Court of the Moscow District).

Bayer filed a final appeal at the SAC and the Presidium granted a request for reconsideration. On April 23, 2013, in a landmark ruling, the Presidium overturned the decisions of the lower courts and sent the case back down for a re-trial. Specifically, the Presidium ruled that the courts must consider the amended patent that results from a partial invalidation of the original patent during a patent infringement proceeding. Moreover, the Presidium held that the delay created between the nullification of an original patent and issuance of an amended patent by ROSPATENT cannot negatively affect the rights of the patentee to enforce its patent. The Presidium also stated that although the original patent was held partially invalid, Bayer did not lose its exclusive right in the invention because the issuance of the amended patent had the same priority date as the original patent. Therefore, the Presidium ruled that dismissal of Bayer’s patent infringement action without consideration of the merits of the scope of the claims in the amended patent was illegal. Thus, the lower courts were ordered to conduct a re-trial. 

This very important decision by the Presidium closes the legislative loophole associated with the imperfect procedure involving the partial invalidation of patents. This decision allows patentees to continue to enforce their patents even if found to be partially invalid as a result of a revocation proceeding.   

This post was written by Lisa Mueller and Vladislav Ugryumov of Gowlings (Moscow).

 

Understanding Biologics and Biosimilars in Turkey

In Turkey, medicinal products, including biologics and biosimilars, can only be marketed once a marketing authorization has been issued by the General Directorate of Pharmaceuticals and Pharmacy of the Ministry of Health (MOH). In order to understand the marketing authorization process in Turkey, it is important to understand how certain terms are defined by the MOH. Important terms include:

1. “Medicinal products” are any natural and/or synthetic active substances or combination of substances (including biological drugs and biosimilar drugs) administered to a human for the purpose of treating and/or preventing disease, making a diagnosis, or correcting or modifying a physiological function. 

2. A “substance” is any matter the source of which can or may be human (such as human blood, products obtained from human blood), animal (such as microorganisms, whole animals, parts of organs, animal secretions, toxins, extracts, blood products), vegetable (such as microorganisms, plants, plant parts, vegetable secretions, extracts), or chemical (such as elements, naturally occurring chemical materials, chemical products obtained by chemical change or synthesis).  

3. An “active substance” is any pharmacological active substance used in medicinal products.  

4. A “registered medicinal product for human use” is a medicinal product, approved by the MOH, which is presented to the market in ready form, in special packaging, with a specific name.  

5. A “biological drug” is a product requiring manufacturing and control procedures as well as a combination of physicochemical biological tests to determine the quality of an active substance and is produced or extracted from a biological source. Examples of a “biological drug” include: (a) immunological products; (b) blood products; (c) products obtained through recombinant DNA technology in prokaryotic and eukaryotic cells, the controlled expression of genes coding for biologically active proteins, including transformed mammal cells, hybridoma and monoclonal antibody methods; (d) advanced medical treatment products which concern manufacturing processes involving biological molecules in which the active substance is produced in whole or in part by means of gene transfer and/or genetically modifying cells for the purpose of advanced biological and/or medical treatment; and (e) reagents from which the active substance is not directly derived, namely, products derived from a culture medium, bovine fetus serum, additives, chromatography, etc.

6. A “biosimilar drug” or “biosimilar product” is a medicinal product which demonstrates similarity to a designated or retained biological (medicinal) reference product (biological reference product) in terms of quality, safety and efficacy. The active substance of a biosimilar drug or product is similar to a biological reference drug. Generally, a biosimilar drug and a biological reference product are used at the same strength to treat the same disease. Typically, the only difference between a biosimilar drug and a biological reference product is the trade name, appearance and packaging.  

7. A “designated or retained biological (medicinal) reference product” or “biological reference product” is a biological drug for which a complete application, including administrative, quality, pre-clinical and clinical data, has been made and approved by a regulatory authority outside of Turkey (such as the FDA or EMA).  

Biologics 

In Turkey, to obtain approval of a new biological product, an applicant must submit a “full” application to the MOH. A “full” application involves providing sufficient information to demonstrate the quality, safety and efficacy of the new biological product for the indications requested. As will be discussed in more detail below, this information includes complete and detailed information regarding the biological product, pre-clinical studies {including toxicity studies, pharmacokinetic studies (PK studies), pharmacodynamic studies (PD studies), local tolerance studies, etc.}, phase I, II and III clinical studies (in all indications for which approval is sought), as well as a risk management plan. The phase I, II and III clinical trials (for either a biological or a biosimilar) can be conducted in a country other than Turkey provided that the clinical trials have been approved by the regulatory authority of that country (such as the FDA, EMA, etc.).  

Some of the information that an applicant must submit to the MOH when seeking approval for a new biological product includes: 

1. The name, permanent address, e-mail, telephone and fax number of the applicant;

2. The name, permanent address, telephone and fax number of the manufacturer; 

3. The name of the medicinal product;

4. The quantitative and qualitative particulars of the constituents of the medicinal product using common terminology (except for the empirical chemical formula) and its international non-proprietary name (INN) as recommended by the World Health Organization (where applicable); 

5. A description of the manufacturing method; 

6. A description of the therapeutic indications, contraindications, adverse reactions, special precautions for use (including descriptions involving use during pregnancy and lactation, interaction with other drugs and other forms of interactions, symptoms, emergency procedures and antidotes in the event of an overdose, special warnings, effects on the ability to drive and use machines, etc.); 

7. The dosage, pharmaceutical form, method and route of administration, shelf life and amount contained in a package; 

8. An indication of the disposal method for waste products (after consideration of the storage conditions of the medicinal product, its administration to patients and the potential risks presented by the medicinal product to the environment); 

9. A description of the control methods used by the manufacturer (including quantitative and qualitative analysis of the constituents and finished products, sterility tests, pyrogen substances, tests for measuring the presence of heavy metals, stability tests, biological and toxicity tests, controls conducted during the intermediate phase of manufacturing, etc.); 

10. Results of physicochemical or microbiological tests;           

11. Toxicological, pharmacological tests and clinical studies (namely, phase I, II and III); 

12. For new medicinal products that are to be imported (rather than manufactured in Turkey), a summary of the product characteristics drafted by the originating company and an indication of the term of validity (there are three different terms of “validity”, specifically, (a) the “proposed” shelf life of the product; (b) the shelf life of the product after the packaging has been opened; and (c) the shelf life of the product after dilution), package insert and a mock-up of the proposed packaging; 

13. For new medicinal products that are to be imported, a document drafted by the originating company, along with a Turkish translation thereof, indicating that the real or legal person importing the product is the sole authorized representative for the manufacture, registration and sale of the product in question or a co-marketing representative, where applicable; 

14. For new medicinal products for which the manufacturing of the product is licensed to a third party, a document drafted by the originating company along with a Turkish translation thereof, indicating that the real or legal person manufacturing the product is the sole authorized representative for the manufacture, registration and sale of the product in question or a co-marketing manufacturer, where applicable; 

15. A good manufacturing practice (GMP) document approved by the MOH or a competent authority of a relevant country (such as the FDA, EMA, etc.), indicating that the manufacturer will manufacture the product in accordance with GMP rules;       

16. In the event that the applicant is not the manufacturer of the new biological product, a notarized toll manufacturing agreement signed with the manufacturer (the agreement must contain the conditions specified in the Regulation on Manufacturing Sites of Medicinal Products for Human Use as published in the Official Gazette dated 23/10/2003, no. 25268); 

17. A list of other countries where an application for the biological product has been submitted for approval by a competent authority (such as the FDA, EMA, etc.) and a certified copy of a Pharmaceutical Product Certificate issued by such authority in any other country or countries where the product has been approved and introduced into the market; 

18. Description of the potential risks to be imposed on the environment by the new biological product upon consideration of the provision of the Regulation on Radiation Safety, enforced by the Decision dated 24/07/1985, no. 85/9727 of the Council of Ministers, the Regulation on the Safe Transportation of Radioactive Substances, published in the Official Gazette dated 10/09/1997, no. 23106, the Regulation on Radiation Safety published in the official Gazette dated 24/03/20002, no. 23999, and the Regulation on the Waste Formed in the Use of Radioactive Substances, published in the Official Gazette dated 02/09/2004, no. 25571;            

19. A summary of the product characteristics as specified in the legislation pertaining to the packaging and labeling and a package insert prepared accordingly, mock-ups of the immediate outer-packaging including the size and design to be used in the market, the original summary of the product characteristics approved by competent authorities in other countries for products imported or manufactured under a license, including the product insert and package mock-ups; and 

20. A list of the countries in which a biological product has been rejected, recalled or suspended by a competent authority or in which the applicant has withdrawn the product, including specific and detailed information regarding the rejection, recall, suspension or withdrawal and the steps taken by the applicant to rectify the problem.    

Biosimilars 

In Turkey, to obtain approval of a “biosimilar product,” an applicant must submit an “abridged” application to the MOH. The “abridged” application must demonstrate that there are no significant differences in terms of the quality, safety or efficacy between the biosimilar product and a biological reference product. In addition, a sponsor of a biosimilar product must comply with the requirements of Annex I of the Turkish Regulation for Approval of Human Medicinal Products, the technical requirements of the European Pharmacopeia monographs and any additional general requirements related to biosimilar products described in the guidelines of the Committee for Human Medicinal Products (CHMP) and the International Committee for Harmonisation (ICH).  

To demonstrate the “quality” of the biosimilar product, the “abridged” application must include complete and detailed information regarding the biosimilar product, including head-to-head comparability studies with the biological reference product. For example, a biosimilar applicant must provide (1) data demonstrating that the active substance of the biosimilar product exhibits molecular and biological similarity to the active substance of the biological reference product; (2) biological activity, immunochemical properties and physicochemical studies; (3) purity and impurity studies, including an impurity profile; (4) stability data; (5) in vitro dissolution studies; and (6) data demonstrating that the pharmaceutical form, strength and route of administration of the biosimilar product and the biological reference product are the same (if they are not the same, then additional data will need to be presented to show comparability). 

In addition, in order to demonstrate safety and efficacy of the biosimilar product, an “abridged” application will need to provide data from pre-clinical and clinical studies. Specifically, with respect to data from pre-clinical studies, an applicant must provide in vivo data showing the comparability of the biosimilar product and the biological reference product with respect to: (1) at least one repeat dose toxicity study (up to four weeks); (2) local tolerance; and (3) PK and PD studies. 

Finally, a biosimilar applicant will need to present comparability data from clinical studies. Specifically, a biosimilar applicant will need to present data from phase I PK and PD studies (the PK and PD studies can be combined provided that the PK/PD relationship is characterized) as well as phase III studies (for each indication for which approval is sought). No phase II clinical trials are required. The clinical trial data submitted can be data from clinical trials conducted outside of Turkey provided that the clinical studies were done with the approval from a competent authority (such as the FDA, EMA, etc.) and are comparative with the biological reference product. In addition, a risk management plan will also be required.   

Data Exclusivity

In Turkey, a biosimilar product cannot be marketed at any point during the period of data exclusivity for a biological reference product. However, according to the Guidelines on Biosimilar Medicinal Products in Turkey, biosimilar products are exempt from the data exclusivity period if “additional” studies, which are not required to be submitted for the biological product, are submitted to the MOH for approval. Interestingly, the regulations are silent as to the type of “additional” studies that would be accepted by the MOH.

In many countries, the periods of patent exclusivity and regulatory data exclusivity are completely independent and separate from each another. However, in Turkey, this is not the case. In Turkey, the period of data exclusivity is tied to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. Specifically, the data exclusivity period for a biological reference product is 6 years from the date of first registration of the product in the European Customs Union {which comprises the member states of the European Union (such as Great Britain, Germany, France, Italy, etc.) as well as some other non-European Union countries (such as Turkey)}. However, this 6 year data exclusivity period is limited to the term of any issued Turkish patent having claims that encompass the active substance of the biological reference product. Specific examples of how the data exclusivity period is calculated are provided below. 

Example 1:  A biological reference product receives marketing approval in Germany in August 2013, which is the date of first marketing approval (date of registration) for the product in any European Customs Union (ECU) country. Marketing approval for the product is granted by the MOH in Turkey in December 2013. A patent covering the biological reference product (a humanized antibody) expires in February 2020 in Turkey. Under this scenario, data exclusivity would be available for the biological reference product in Turkey until August 2019. 

Example 2:  A biological reference product receives marketing approval in the Netherlands in August 2011, which is the date of first marketing approval (date of registration) for the product in any ECU country. Marketing approval for the product is granted by the MOH in Turkey in August 2013.  A patent covering the biological reference product (a humanized antibody) expired in March 2012 in Turkey. Under this scenario, no data exclusivity would be available for the biological reference product in Turkey. 

Example 3:  A biological reference product receives marketing approval in Great Britain in August 2013, which is the date of first marketing approval (date of registration) for the product in any ECU country. Marketing approval for the product is granted by the MOH in Turkey in December 2013. A patent covering the biological reference product (a humanized antibody) expires in October 2016 in Turkey. Under this scenario, data exclusivity would be available for the biological reference product in Turkey until October 2016. 

Biosimilars in Turkey

To date, two biosimilars have been approved by the MOH in Turkey. The first is “Leucostim” (the licensee of which is Dem İlaç, a Turkish pharmaceutical company, and the manufacturer is DONG-A PHARM. CO., LTD., a South Korean pharmaceutical company) which contains the active substance filgrastim. The second is “Epobel” (the licensee is Nobel İlaç, a Turkish pharmaceutical company, and the manufacturer is STADA Arzneimittel AG, a German pharmaceutical company) which contains the active substance epoetin zeta.

This article was written by Laura Opperman, Lisa Mueller and Canan Ozturker and Aydin Deris from Deris Patents & Trademarks Agency A.S.

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Understanding Biologics and Biosimilars in Brazil

In Brazil, only new biological products and biological products (including biosimilars) registered with the National Agency of Sanitary Surveillance (ANVISA) and manufactured or imported by companies authorized by the Federal government and licensed by the state government may be sold and distributed. ANVISA’s responsibilities include overseeing the development, manufacturing and marketing of products and services that are subject to sanitary surveillance and controls relating to matters at ports, airports and borders.

In order to understand the approval process for biologics and biosimilars in Brazil, it is important to understand how certain terms are used by the ANVISA and other governmental agencies. Important terms include:

1. A “biological product” is a biological that is not new or is known and contains a molecule with known biological activity that is already registered in Brazil (namely, with ANVISA) and has undergone all stages of manufacturing (namely, formulation, bottling, lyophilization, labeling, packaging, storage, quality control and release of the biological product batch for use). The following are considered to be “biological products”:

      a.  Vaccines;

b. Hyper-immune serums (which are defined as whole or fragmented heterologous, purified immunoglobulins, obtained from the plasma of hyper-immunized animals with toxic substances that originated from animals, microorganisms or viruses);

c. Hemoderivatives (which are defined as pharmaceutical products obtained from human plasma, subjected to industrialization processes and standardization to provide quality, stability, activity and specificity);

d. Biodrugs which are classified into:

i. Drugs obtained from biological fluids or tissues of animal origin; and

ii. Drugs obtained by biotechnological procedures;

e. Monoclonal antibodies; and

f. Drugs containing live, attenuated or dead microorganisms.

2. A “new biological product” is a biological product containing molecules with known biological activity that are not registered in Brazil (namely, with ANVISA) and that have undergone all stages of manufacturing (namely, formulation, bottling, lyophilization, labeling, packaging, storage, quality control and release of the new biological drug batch for use).

3. A “comparer biological product” is a biological product already registered with ANVISA based on submission of a complete dossier and that has already been sold in Brazil.

4. A “complete dossier” is the full set of documents submitted to ANVISA to demonstrate the attributes of quality, safety and efficacy of a biological product. The dossier is made up of the full characterization of the product and detailed description of the production process, demonstrating the consistency in the manufacturing of the drug in addition to the substantial evidence of clinical safety and efficacy demonstrated through nonclinical and clinical studies (phases I, II, and III).

Registration of new biological products or biological products

To register a new biological product or a biological product, an applicant company (applicant) must file a registration application (which must be submitted in Portuguese with one copy of the entire application being provided on a CD-ROM in a pdf format). Any documents included in a foreign language must be translated.

Specifically, an applicant is required to submit the following documents:

1. Registration application forms – fp1 and fp2;

2. An original copy of proof of payment of the health surveillance inspection fee;

3. A declaration of the economic capacity of the applicant;

4. A copy of applicant’s business license and/or health permit;

5. A copy of applicant’s business authorization certificate/form or its publication in the federal official gazette;

6. A copy of an updated technical responsibility certificate issued by a regional pharmacy board evidencing that the manufacturer has assistance from a pharmacist in charge (who is qualified for such a purpose);

7. Technical justification for the biological product’s registration;

8. A copy of the good manufacturing practices certificate (GMPC) issued by ANVISA for all manufacturers of the active ingredient, bulk biological product, biological product in its primary packaging and the finished biological product, diluent and adjuvant;

9. A copy of the GMPC issued by the competent health authority in the country where the manufacturer of the active ingredient, bulk biological product, biological product in its primary packaging and the finished product, diluent and adjuvant is located;

10. A history of the biological product registration status in other countries, where applicable;

11. A copy of proof of registration in the country of origin of the biological product, issued by the respective competent health authority;

12. A copy of the package insert approved by the health authority in the country of origin, accompanied by a sworn translation;

13. The package insert and primary and secondary package models as required by the legislation currently in effect;

14. Updated pharmacoviligance data, as required by the legislation currently in effect, obtained from clinical studies and product sales, when applicable;

15. Barcodes (or other identification) and safety mechanisms to enable tracing of the biological product as required by the legislation currently in effect;

16. A copy of the national, international or internal compendium of the applicant with a description of the finished biological product’s specifications;

17. Additional information according to the legislation in effect on transmissible spongiform encephalopathy control, when applicable;

18. A technical report (discussed in more detail below);

19. A therapeutic experimentation report; and

20. A pharmacovigilance report.

The technical report that must be submitted must contain the following information:

1. The name and address of the manufacturer and the cell bank storage location;

2. The name and address of all manufacturers of the active ingredient, bulk biological product, biological product in its primary packaging and the finished biological product, diluent and adjuvant;

3. The name and address of the party that issued the finished product batch release certificate;

4. The following general data on the biological product:

a. Dosage form presentation;

b. A full description of the formula of the biological product, with all its components specified by the corresponding technical names and synonyms according to the Brazilian common denomination or international common denomination or, in its absence, a denomination of the chemical abstracts services, including the units of measurement used;

c. The functions performed by each substance in the formula;

d. The route(s) of administration;

e. Directions for use, when applicable;

f. Indications, purpose or intended use;

g. Contraindications;

h. Side effects;

i. Adverse reactions;

j. Restrictions or cares to be considered;

k. Precautions or warnings;

l. Drug and food interactions;

m. Change in the lab tests;

n. Signs, symptoms and conduct (in cases of overdose);

o. Expiration date;

p. Preservation/storage care;

q. Preservation/storage temperature;

r. Transportation temperature;

s. Specifications regarding the primary and secondary packaging material; and

t. Codes or conventions used by the applicant to identify the active ingredient batches, bulk biological product, the biological product in its primary packaging and finished biological product;

5. A history of the development of the biological product, including a description of the purpose for each batch produced (namely, for use in stability studies or preclinical or clinical studies);

6. Information on the various stages of manufacturing, including:

a. A summarized production protocol in the form of a flowchart that identifies the controls in the process;

b. A list of the main equipment used in the manufacturing;

c. A detailed description of all stages of manufacturing of the biological product, diluent and adjuvant;

d. Identification and justification for the selection of the critical stages of the manufacturing process;

e. A description of the controls in place and a justification for the determination of these specifications;

f. A scale of production in all manufacturing stages indicating the minimum and maximum size of the industrial batch to be produced for sale;

g. A description and justification for the changes made in the production process during the development of the finished biological product;

h. A validated report of the procedures used to remove and/or eliminate viruses, when applicable;

i. A validated report of the critical stages of the manufacturing process; and

j. Validation and justification for any reprocesses;

7. Information on quality control, including:

a. A description of all quality control tests conducted (including all tests conducted on the active ingredient to the final product);

b. A description of the reference standards used;

c. Validation of the analytical methodologies used as required by the health legislation currently in effect; and

d. A reference and justification for each specification determined in the quality control tests;

8. A description of the storage requirements for the active ingredient, bulk biological product, intermediary biological product, biological product in its primary packaging and the finished biological product, diluent and adjuvant;

9. A description for recipients and storage forms for the active ingredient, bulk biological product, intermediary biological product, biological product in its primary packaging and the finished biological product, diluent and adjuvant and the conditions to be maintained to assure the biological product quality;

10. Transport chain validation, including:

a. Operation and performance qualifications of the boxes to be used for transport and validated transport procedures for the active ingredient, bulk biological product, intermediary biological product, biological product in its primary packaging and the finished biological product, diluent and adjuvant; and

b. Operation and performance qualifications of the boxes to be used to transport the finished biological product in the national territory;

11. A description of the solutions, components and culture mediums used to manufacture the biological product;

12. Information on the excipients, including:

a. A description of the physical, chemical, microbiological properties and other quality control information;

b. The specification of each excipient;

c. A description of the possible chemical interactions of each excipient with the active ingredient; and

d. A study demonstrating the efficacy of any preservatives used (for any biological product that contains a preservative in the final formula);

13. A report detailing the stability studies (including the protocol) conducted according to the health legislation currently in effect;

14. Information on contaminants and impurities, including:

a. A characterization of the contaminants and impurities;

b. A description of the processes used to reduce/remove impurities that originate from the biological product breakdown or from the manufacturing process;

c. Justification for any impurity specifications in the finished product; and

d. A safety evaluation of adventitious agents from the starting materials of biological origin; and

15. The primary and secondary packaging description and specifications.

Routes for approval for new biological products and biological products in Brazil

There are two routes by which a biological product registration may be filed:

1. Individual development route (used for new biological products and biological products); or

2. Comparability route (used for biological products, namely, biosimilars).

Individual Development Route

An applicant can seek regulatory approval for a new biological product or a biological product pursuant to the “individual development route.” Under the “individual development route,” not only must an applicant present all of the above information, but the applicant must provide a full report of all nonclinical studies as well and the complete protocols and reports of clinical studies (namely, phase I, II and III studies). Additionally, if available, data from phase IV clinical studies should be presented. An applicant submitting a new biological product or biological product registration application under this route must submit sufficient information and data (through nonclinical and clinical studies) to demonstrate the quality, safety and efficacy of the new biological product or biological product.

With respect to the nonclinical studies, the extent of these studies may be reduced depending on the complexity and the level of characterization of the molecule and the extent of the characterization of the biological product’s impurity level, toxicity potential and therapeutic index. Regarding clinical studies, phase I, II and III studies are required with phase III studies being absolutely mandatory. Clinical studies may be conducted in or outside Brazil. For clinical studies conducted outside of Brazil, the studies must be approved by the health authority in the country where the clinical research was conducted (such as by the FDA, EMA, etc). For clinical studies conducted within Brazil the following approvals must be obtained prior to the commencement of any study:

1. Ethical approvals must be obtained from the clinical ethics committee (CEP) and the National Commission for Ethics in Research (CONEP) of each coordinating site (Brazil does not have any institutional review boards); and

2. Clinical protocol approvals must be obtained from ANVISA {ANVISA’s approval is required because it is responsible for issuing an import license for the biological product as well as an official approval document (known as the “Special Communicate” which is a single document which contains the approval of the clinical protocol as well as ANVISA’s official approval)}.

Brazil does not require that the phase I and II studies be comparative; however, phase III studies must be comparative when an application is for a new biological product (except in the case of hemoderivatives, vaccines and biological products having an oncology indication).

Comparability Route (Biosimilars)

An applicant can seek regulatory approval for a biological product pursuant to the “comparability route.” The “comparability route” is a regulatory route that an applicant can use to obtain registration for a biological product by demonstrating comparability in terms of quality, efficacy and safety between a biological product and a “comparer biological product.”

When an applicant files a biological product registration application under this route, not only must the applicant present all of the above information (namely, the detailed application and technical report), but must also submit the following documents:

1. A report with data on the biological product, including the following, mandatory information:

a. A description of the analytical techniques used to detect any potential differences between the biological product and the comparer biological product; and

b. Data on the biological, physical and chemical characterizations related to the quality attributes of the biological product;

2. A declaration providing the name of the comparer biological product;

3. A declaration with evidence demonstrating that the same comparer biological product was used during the biological product’s development studies;

4. Information on the expression system used to manufacture the biological product and the comparer biological product;

5. A comparison of the molecules comprising the biological product and the comparer biological product;

6. Reports on the comparative analysis between the main active ingredients, whenever required;

7. A report containing a detailed description of head-to-head comparability tests, with an indication of the capacity of the tests to detect differences in the quality attributes between the biological product and the comparer biological product;

8. Reports of the comparative stability studies that have been generated in accelerated and under stress conditions according to the legislation in effect;

9. A report containing a description of the differences observed in the purity and impurity profile between the biological product and the comparer biological product;

10. An evaluation of the contaminants and impurities identified in the biological product and a discussion of their potential impact on the quality, safety and efficacy of the biological product;

11. An analytical characterization of the biological product and the comparer biological product;

12. Results of comparative biological tests to determine the level of comparability between the biological product and the comparer biological product; and

13. A conclusive report, including a demonstration of comparability, containing sufficient information to predict if the differences detected in the quality attributes result in an adverse impact on the safety and efficacy of a biological product.

All studies in a development program where registration is sought for a biological product through the comparability route must be of a comparative nature. Also, a biological product may not be considered to be comparable if the analytical procedures used are not sufficient to point out any relevant differences that could impact the safety and efficacy of the biological product and/or the relationship between specific quality attributes, safety and efficacy have not been established.

In addition to providing all of the above information, an applicant must also submit complete reports of nonclinical studies. The nonclinical studies must be comparative and designed to detect significant differences between the biological product and the comparer biological product.  Specifically, an applicant must submit reports of the following in vivo nonclinical studies:

1. Relevant pharmacodynamic studies for the therapeutic indication intended; and

2. Cumulative toxicity studies (including at least one repeated dose), including a characterization of the parameters of toxicity kinetics conducted in a relevant animal species.

In addition to the nonclinical studies, an applicant must submit reports of the following clinical studies (including the protocols):

1. Pharmacokinetic studies;

2. Pharmacodynamic studies; and

3. Pivotal clinical safety and efficacy studies (namely, Phase III studies).

The pharmacodynamic and pharmacokinetic clinical studies can be combined provided that the pharmacokinetic/pharmacodynamic relationship is characterized. However, any comparative clinical studies must demonstrate the comparability in terms of the safety and efficacy profiles between the biological product and the comparer biological product. Moreover, the design and comparability margins of any safety and efficacy studies must be statistically and clinically supported. Finally, data from a phase IV study must also be submitted if available.

Biosimilars approved in Brazil 

            Approximately 187 biosimilar applications have been approved by ANVISA. Examples of some of the biosimilars that have been approved and registered (namely, received marketing authorization by ANVISA) include:

1. Somatropin (a growth hormone) which is marketed by Sandoz Do Brasil Indústria Farmacêutica LTDA, Merck S/A, Laboratorios Pfizer LTDA, Laboratório Químico Farmacêutico Bergamo LTDA Bergamo LTDA, Biosintética Farmacêutica LTDA, Novo Nordisk Farmacêutica Do Brasil LTDA and Aspen Pharma Indústria Farmacêutica LTDA;

2. Filgrastim (a granulocyte colony-stimulatory factor) which is marketed by Produtos Roche Químicos e Farmacêuticos S.A, Laboratório Químico Farmacêutico Bergamo LTDA, Blausiegel Indústria e Comércio LTDA, Dr. Reddys Farmacêutica Do Brasil LTDA, Teva Farmacêutica LTDA, and Biosintética Farmacêutica LTDA;

3. Enoxaprin (a low molecular weight heparin) which is marketed by EUROFARMA Laboratórios S/A, Instituto Biochimico Indústrua Farmacêutica LTDA, Cristália Produtos Químicos Farmacêuticos LTDA, Sanofi-Aventis Farmacêutica LTDA, Blausiegel Indústria e Comércio LTDA and Aspen Pharma Indústria Farmacêutica LTDA;

4. Etanercept (a fusion protein) which is marketed by Wyeth Indústria Farmacêutica LTDA; and

5. Recombinant erythropoietin (a hormone) which is marketed by Biosintética Farmacêutica LTDA and Chron Epigen Indústria e Comércio LTDA.

Availability of regulatory/data exclusivity for biologics in Brazil

Brazilian law does not provide for specific periods (or “periods of non-reliance”) during which third parties are prohibited from obtaining registration (namely, marketing approval) for a biological product (biosimilar) from ANVISA by referring to an originator’s data for a comparer biological product. According to Law nº 10,603, data/regulatory exclusivity periods in Brazil are only available for pharmaceutical products relating to veterinarian use, fertilizers, agrochemicals, their components and the like. Therefore, Brazilian law does not provide any regulatory/data exclusivity periods for new pharmaceuticals (small molecules) or new biological products (biologics) for human use.

Thus, in practice, ANVISA will register any generic drug (such as a branded or non-branded small molecule) or biological product (biosimilar) for human use anytime after the registration of a new drug or new biological product (biologic). The only option available for an originator to try and secure regulatory/data exclusivity for its new drug or biologic would be by filing a lawsuit against ANVISA.

This post was written by Lisa Mueller and Gustavo de Freitas Morais of Danneman Siemsen.