Biologics and Biosimilars Bits and Bytes – January 8, 2016

Revised Indian Biosimilar Guidelines Expected Soon

According to reports, the Indian Ministry of Health is planning on releasing revised guidelines on the approval of “similar biologics” sometime in February/March 2016. India’s biosimilar guidelines became effective on September 15, 2012. It is believed that the revised guidelines will address a host of items including increased requirements regarding comparability testing with a reference drug product, as well as various ethical questions.

U.S. FDA Approves a “Similar” but not a “Biosimilar” version of Lantus®

On December 16, 2015, the U.S. Food and Drug Administration (FDA) announced that it had approved Eli Lilly/Boehringer Ingelheim’s (Lilly) Basaglar® product as the first “follow-on” insulin glargine product for use in improving glycemic control in adult and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus.  Basaglar® is the first insulin product approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act. Specifically, Lilly submitted a 505(b)(2) application for Basaglar® that relied, in part, on the FDA’s finding of safety and effectiveness of Sanofi’s Lantus® for its approval. While similar to Lantus®, Basaglr® was not approved as a biosimilar. In contrast, in Europe, on September 9, 2014, the European Medicines Agency approved Lilly’s product as a biosimilar under the brand name Abasaglar (originally approved under the brand name Abasria).

While Basaglar® received tentative approval from the FDA in August 2014, a 30-month hold was placed on its market entry because of a patent infringement dispute with Sanofi which was settled in September 2015.

This post was written by Lisa Mueller.

Biologics and Biosimilars Bits and Bytes – December 10, 2015

Amgen files for first European Approval of a Biosimilar to Humira®

On December 4, 2015, Amgen Inc. (Amgen) announced the filing of a Marketing Authorization Application (MAA) with the European Medicines Agency (EMA) for ABP 501, a biosimilar version of AbbVie Inc.’s (AbbVie) Humira® (adalimumab). According to Amgen, its MAA submission included analytical, clinical and pharmacokinetic data. Amgen conducted Phase 3 comparative efficacy and safety studies in both moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis patients. Amgen indicated that its Phase 3 studies met their primary endpoints showing clinical equivalence to Humira®. The safety and immunogenicity of ABP 501 was also comparable to Humira®. Additionally, data to support the transition of Humira® patients to ABP 501 was also included in the filing.

This MAA filing follows Amgen’s November 25, 2015 filing of a 351(k) application with the U.S. Food and Drug Administration (FDA) for ABP 501.

Coherus Files Two New IPR Petitions against AbbVie’s Patents Covering Humira®

On December 7, 2015, Coherus Biosciences Inc. (Coherus) filed two new IPR petitions, IPR2016-00188 and IPR2016-00189, against AbbVie’s U.S. Patent Nos. 9,017,680 and 9,073,987 covering Humira®. These filings come almost a month after the November 9th filing by Coherus of IPR petition, IPR2016-00172, against another AbbVie patent covering Humira®, U.S. Patent No. 8,889,135. Coherus’ three IPR petitions can be found here: 1. IPR201600188 2. IPR201600189 3. IPR201600172. This brings the total number of IPR petitions filed against AbbVie patents covering Humira® to five. Earlier this year, on June 26, 2015 Amgen filed IPR petitions, IPR2015-01514 and IPR2015-01517 against two other AbbVie patents, U.S. Patent Nos. 8,916,157 and 8,916,158.

Infliximab Biosimilar Approved in Korea

On December 4, 2015, Samsung Bioepis Co., Ltd., (Samsung Bioepis) announced that Korea’s Ministry of Food and Drug Safety (MFDS) approved Renflexis®, a biosimilar version of Remicade® (infliximab), also known as SB2. Renflexis® was approved for the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn’s disease, pediatric Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis, psoriatic arthritis and plaque psoriasis. This is the second biosimilar approved in Korea for Samsung Bioepsis, a joint venture between Biogen and Samsung Biologics. The first approval was in September 2015 for Brenzys®, a biosimilar version of Enbrel® (etanercept), also known as SB4.

In February 2013, Samsung Bioepis and Merck & Co. (Merck) announced a development and commercialization agreement under which Merck would commercialize multiple pre-specified and undisclosed biosimilar products in certain partnered territories. Under terms of the agreement, Samsung Bioepis was responsible for preclinical and clinical development, process development and manufacturing, clinical trials and regulatory registration. Merck was responsible for commercialization. As a result, Merck will commercialize Renflexis® in South Korea and plans to launch in the first half of 2016.

This post was written by Lisa Mueller.


Biologics and Biosimilars Bits and Bytes – November 30, 2015

As our BRIC Wall readers are aware, biologics and biosimilars are becoming more newsworthy and noteworthy around the world. To help our readers stay current, we are introducing a new feature – Biologics and Biosimilars Bits and Bytes – to provide periodic updates on the most significant developments. We hope you find this new feature informative.

Amgen Files for First U.S. Approval of a Biosimilar to AbbVie’s Humira®

On November 25, 2015, Amgen filed a 351(k) application with the U.S. Food and Drug Administration (FDA) for ABP 501, a biosimilar version of AbbVie Inc.’s (AbbVie) Humira® (adalimumab). The filing was noteworthy not only because it is believed to be the first biosimilar application filed in the U.S. for adalimumab, but also because it was Amgen’s first submission of any biosimilar application to the FDA.

Adalimumab is a human monoclonal antibody that is used to treat autoimmune diseases. It works by binding to tumor necrosis factor (TNF)-alpha preventing it from activating TNF receptors (which cause the inflammatory reactions associated with autoimmune diseases). Adalimumab has been approved for the treatment of rheumatoid, juvenile idiopathic and psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, psoriasis and ulcerative colitis. In 2014, worldwide sales reached almost $13 billion.

According to Amgen, its submission included analytical, clinical and pharmacokinetic data. Phase 3 comparative efficacy and safety studies were conducted in both moderate-to-severe plaque psoriasis and moderate-to-severe rheumatoid arthritis patients. These studies met their primary endpoints demonstrating clinical equivalence to adalimumab. Additionally, the submission also included data to support the switching of adalimumab patients to ABP 501.

In addition to Amgen, a number of other companies are developing biosimilar versions of adalimumab. These include: Boehringer Ingelheim (for BI695501), Baxalta and Momenta Pharmaceuticals (for M923), Samsung Bioepsis (for SB5) and Oncobiologics (for ONS-3010).

The EMA Recommends the first Enbrel® Biosimilar for Approval In Europe

On January 21, 2015, Samsun Bioepis, a joint venture between Samsun Biologics and Biogen, filed for approval of Benepali™ (etanercept), also known as SB4, by the European Medicine Agency (EMA). On November 19, 2015, the EMA’s Committee for Medicinal Products for Human Use (CHMP), recommended Benepali™ for marketing authorization. If approved, this will bring the first biosimilar of Enbrel® to market in Europe.

Etanercept is a fusion protein that inhibits the activity of tumor necrosis factor alpha. The CHMP recommended Benepali™ for use:

  1. In combination with methotrexate for treatment of moderate to severe rheumatoid arthritis in adults that have an inadequate response to disease-modifying anti-rheumatic drugs, including methotrexate;
  2. Alone in adults intolerant to methotrexate or when continued treatment with methotrexate is not appropriate;
  3. In the treatment of active and progressive psoriatic arthritis in adults who fail to respond to disease-modifying anti-rheumatic drugs;
  4. In the treatment of severe active ankylosing spondylitis in adults who have had an inadequate response to conventional therapy;
  5. In the treatment of severe nonradiographic axial spondyloarthitis with objective signs of inflammation in adults who have had an inadequate response to nonsteroidal anti-inflammatory drugs; and
  6. In plaque psoriasis in adults with moderate to severe psoriasis who fail to respond to, who have a contraindication to, or who are intolerant to other systemic therapy (such as ultraviolet A light, methotrexate, psoralen, ciclosporin, etc.).

The CHMP’s recommendation will now be referred to the European Commission which grants approval for the European Union, Iceland and Norway. Final approval is anticipated by February 2016. Once final approval is received, Benepali™ will be commercialized in Europe and Switzerland by Biogen which also holds the commercialization rights in Japan. Merck & Co. will commercialize in all other markets except the U.S.

This post was written by Lisa Mueller.

TPP and the Continuing Controversy Over the Exclusivity Period for Biologics

This is our third post examining certain of the patent related provisions of the Trans-Pacific Partnership (TPP) from the WikiLeaks released final “agreed version of the TPP chapter on intellectual property rights.”  Our first post, which examined patentable subject matter and grace periods, can be found here.  Our second post, which examined the provisions relating to patent revocation, publication of patent applications and procedures for adjusting patent term due to an unreasonable delay by a patent office, can be found here. In this post, we examine the controversial provisions relating to the exclusivity period for biologics.

The exclusivity period for biologics was one of the major issues that held up the negotiations of the TPP. During the negotiations, the U.S. and Japan favored longer periods of exclusivity (up to 12 years) while Australia and New Zealand favored shorter (up to five years).

What is the difference between data and market exclusivity?

Data exclusivity refers to the period of time following market approval during which a biosimilar manufacturer cannot use the safe and efficacy data (such as preclinical and clinical trial information) of an innovator company. For example, in the U.S., a biosimilar application cannot be submitted to the U.S. Food and Drug Administration (FDA) during the period of data exclusivity (which is four years).

In contrast, market exclusivity refers to the period during which a biosimilar manufacturer cannot be approved for sale; however, a biosimilar manufacturer may use the data of the innovator company for review of its regulatory application. Currently, the U.S. FDA provides eight years of market exclusivity for biologics. The four-year data exclusivity plus the eight-year market exclusivity provides for a total exclusivity period in the U.S. of 12 years.

Article QQ.E.20 of the TPP

The exclusivity period for biologics is provided in Article QQ.E.20 of the TPP which is reproduced below.

Article QQ.E.20: {Biologics}

1. With regard to protecting new biologics, a Party shall either:

(a) with respect to the first marketing approval in a Party of a new pharmaceutical product that is or contains a biologic, provide effective market protection through the implementation of Article QQ.E.16.1 and Article QQ.E.16.3 mutatis mutandis for a period of at least 8 years from the date of first marketing approval of that product in that Party; or alternatively

(b) with respect to the first marketing approval in a Party of a new pharmaceutical product that is or contains a biologic, provide effective market protection:

(i) through the implementation of Articles QQ.E.16.1 and QQ.E.16.3 mutatis mutandis for a period of at least 5 years from the date of first marketing approval of that product in that Party;
(ii) through other measures; and
(iii) recognizing that market circumstances also contribute to effective market protection

to deliver a comparable outcome in the market.

2. For the purposes of this Section, each Party shall apply this provision to, at a minimum, a product that is, or alternatively, contains, a protein produced using biotechnology processes, for use in human beings for the prevention, treatment or cure of a disease or condition.

3. Recognizing that international and domestic regulation of new pharmaceutical products that are or contain a biologic is in a formative stage and that market circumstances may evolve over time, the Parties shall consult after 10 years, or as otherwise decided by the TPP Commission, to review the period of exclusivity provided in paragraph 1 and the scope of application provided in paragraph 2, with a view to providing effective incentives for the development of new pharmaceutical products that are or contain a biologic, as well as with a view to facilitating the timely availability of follow-on biosimilars, and to ensuring that the scope of application remains consistent with international developments regarding approval of additional categories of new pharmaceutical products that are or contain a biologic.

A choice between one of two alternatives

Article QQ.E.20, provides countries with two options for providing a biologics exclusivity period. These options are:

1. A period of at least eight years from the date of first marketing approval; or
2. A period of at least five years from the date of first marketing approval as well as “protection through other measures,” (while recognizing that “recognizing that market circumstances also contribute to effective market protection.”)

Regardless of the option a country chooses, the article is clear that the option selected must provide a “comparable” outcome in the market. Because the article provides varying transition periods for each country, these provisions will come into effect gradually during the next decade. Interestingly, the article also provides that the parties to the agreement will consult after 10 years (unless otherwise decided by the TPP commission), to review the period of exclusivity.

Does the TPP provide data exclusivity, market exclusivity or both?

The provisions of Article QQ.E.16.1 and Article 16.3 as well as Article QQ.E.20, appear to provide only “market” exclusivity for biologics. It is currently unclear whether or not any period of “data” exclusivity can be built into the eight-year period recited under Article QQ.E.20.

Other items of concern

Under the second option, Article QQ.E.20 provides that exclusivity for biologics can be achieved “through other measures.” It is unclear what those provisions might be. In addition, the article also refers to a “comparable outcome in the market.” Given the price tags of biologics, it is hard to see how a three-year difference could result in a comparable outcome.

What has changed?

Not much. Several countries will not have to make any changes to their laws providing biologic exclusivity. For example, the U.S. will not have to shorten its 12-year exclusivity period and Japan and Canada, which each provide eight-years exclusivity, will be able to maintain that number as well. Australia and New Zealand have indicated that their five-year exclusivity periods meet the requirements of the TPP and expect no change. While Mexico did not have any specific legislation providing for data protection for biologics, Mexican courts have been contemplating the possibility of having the period of five years pursuant to NAFTA as the minimum period of protection. Of all the signatories to the TPP, only Brunei currently provides less than five years of exclusivity.

What has the reaction been and where do we go from here?

As with most things, the reaction the TPP in the U.S. depends on who you ask. Both the Biotechnology Industry Organization (BIO) and Pharmaceutical Research and Manufacturers of America (PHARMA) expressed disappointment that the TPP failed to include a 12-year exclusivity period. BIO expressed concern that while the TPP would not impact the 12-year exclusivity period in the U.S., it might “chill global investment” and slow the development of new biologics. Doctors without Borders were far more critical stating that “the TPP will still go down in history as the worst trade agreement for access to medicines in developing countries.”

Hillary Clinton has stated that she believes that pharmaceutical companies got more benefits and consumers fewer. Senator Orrin Hatch (a supporter of the 12-year exclusivity period) has expressed concern that the TPP does not provide enough protection to foster global innovation. On November 20th, House Speaker Paul Ryan expressed concern about the level of intellectual property protection available for biologics in the TPP as well as other aspects of the agreement. Specifically, he stated, “I’m concerned about biologics, quite frankly. There’s other issues I’m concerned about.” He indicated that he believes that Congress can vote on the TPP in 2016 but he is not sure when. Moreover, he stressed that he wants to ensure that the deal meets the objectives set out by Congress in the Trade Promotion Authority (TPA) law. He stated, “Let me back up and say one thing: getting it right matters. This will be the largest trade agreement. It’s 40 percent of gross domestic product. And the goal here, and the reason why we passed TPA is because we need to be writing the rules of the global economy.” Speaker Ryan also made it clear that the TPP should ensure strong IP protections around the world.

Time will tell when and if Congress will vote on the TPP in 2016. Additionally, given that several members of Congress are unhappy with the exclusivity provisions for biologics in the TPP, it will be interesting to see whether or not the Obama administration will have to renegotiate the biologics provisions to ensure greater protection for biologics.

This post was written by Lisa Mueller.

Jordan FDA Issues a Guideline for the Registration of Biosimilars

Recently, the Jordan Food and Drug Administration (JFDA) issued a guideline regarding the registration of biosimilars. Much of the information used to develop the guideline was adopted from the European Medicines Agency (EMA) guidelines.


The guideline defines “reference product” and “biosimilar product” as follows:

“Reference product” refers to an innovator biological medicinal product already approved/registered in the reference countries in the European Union (via the centralized procedure), U.S.A., Australia, Canada and/or Jordan based on complete dossier (containing full quality, safety and efficacy information). The reference product is used in demonstrating the comparability of a biosimilar product through quality, non-clinical and clinical studies.

“Biosimilar product” or “similar biological medicinal product” refers to a biological medicinal product that is similar to the reference product in terms of its quality, safety and efficacy, and contains a version of the active substance that is similar, in molecular and biological terms, to the active substance. The posology and route of administration of the biosimilar product must be the same as those of the reference medicinal product. Any deviations from the reference product in terms of strength, pharmaceutical form, formulation excipients or presentation requires justification. If needed, additional data should be provided. Any difference between the biosimilar product and the reference product should not compromise safety.

Scope and application

As in other jurisdictions, the guideline makes clear that the aim of the biosimilar approach in Jordan is to demonstrate close similarity of a biosimilar product in terms of quality, safety and efficacy to a reference product. The guideline states that the information requirements outlined for demonstrating similarity apply to biologic drugs that contain, as active substances, well characterized proteins derived through modern biotechnological methods, such as recombinant DNA, in microbial or eukaryotic cell culture. The guideline further states that the “biosimilar approach” is often more difficult to apply to other types of biologics that are more complex, more difficult to characterize and for which little clinical regulatory experience has been obtained thus far. Therefore, the guidelines do not cover “complex” biologics such as blood-derived products, vaccines, immunologicals/allergens and tissue, gene and cell therapy products.

In Jordan, as in other jurisdictions, a biosimilar manufacturer is required to conduct a direct and extensive comparability exercise between the biosimilar product and the reference product in order to demonstrate that the two products have a similar profile in terms of quality, safety and efficacy. Only one reference product can be used during a comparability exercise and a biosimilar product cannot be used as a reference product. Additionally, eligibility for a biosimilar pathway hinges on the ability to demonstrate similarity to a reference product. Biosimilar products that employ clearly different approaches of manufacturing compared to the reference product (such as, for example, the use of transgenic organisms versus cell culture), will only be eligible for approval if justified. Additionally, approval of a biosimilar product is not an indication that the product can be automatically substituted for the reference product.

The guideline provides non-clinical and clinical requirements for biosimilar products that demonstrate similarity to a reference product based on the results from comparability exercises from chemistry, manufacturing and control (CMC) perspectives. When similarity of a potential biosimilar product cannot be adequately established, the applicant should submit the product as a stand-alone biotechnological product with a dossier containing complete non-clinical and clinical data.

The non-clinical and clinical issues with respect to specific products are further provided in the product-class specific guidelines. According to the guidance, if the comparability exercise is supported by state-of-the art analytical systems, the quality level may allow for a reduction of the non-clinical and clinical data requirements compared to a full dossier. Nonetheless, the guidance makes clear that a case-by-case approach will be used depending on the level of clinical experiences with the substance class. Additionally, in principal, extrapolation from one indication to another is possible, but would need to be scientifically justified.

Finally, the guideline recommends that biosimilar applicants seek advice from the JFDA before submitting their biosimilar application.

Specific information regarding the comparability exercise

According to the guideline, the following should be considered by a biosimilar applicant during a comparability exercise:

  1. The comparative quality, non-clinical and clinical studies need to substantiate the similarity of the structure/composition, quality, efficacy and safety as well as the immunogenicity of the biosimilar and the reference product.
  2. The pharmaceutical form, strength, dosage and route of administration of the biosimilar product should be the same as that of the reference product. Any differences between the two should be justified by appropriate studies made on a case-by-case basis.
  3. Comparability of a chosen reference product should be addressed for both the active substance and the drug product.
  4. It is not expected that the quality attributes of the biosimilar product and the reference product will be identical. Minor structural differences in the active substances such as variability in post-translation modifications may be acceptable provided that such variability is justified and supportive information is provided demonstrating that such differences will not affect the clinical safety, efficacy and immunogenicity should be provided.
  5. Quality differences may impact the amount of non-clinical and clinical data needed (which will be assessed on a case-by-case basis).
  6. The purpose of the comparability exercise is to demonstrate that the biosimilar product and the reference product are similar at the level of the finished product.
  7. If, for some analytical techniques, a direct or side-by-side analysis of the biosimilar and reference medicinal product is not feasible or gives limited information (such as due to the low concentration of the active substance and/or the presence of interfering excipients such as albumin), samples could be prepared from the finished product. In such instances, the techniques used to prepare the samples should be outlined, and their impact on the samples should be appropriate documented and discussed (namely, a comparison of the active substances before and after formulation preparation).
  8. A representative number of batches produced according to a manufacturing process with proven consistency for intended commercial use should be used in all comparability studies.

Quality standards

The guideline states that a biosimilar product derived from a separate and independent master cell bank using an independent manufacturing and control methods must meet the same quality standards as an innovator product. As a result, a fully quality dossier will always be required. Additionally, a biosimilar manufacturer will be required to submit extensive data focused on the similarity, including comprehensive side-by-side physicochemical and biological characterization of the biosimilar and the reference product. Moreover, due to the limitations of analytical techniques and the unpredictable nature of the clinical consequences of any structural or biophysical differences, it was not possible for the JFDA to define the exact degree of biophysical similarity that will be considered “sufficiently similar” for a product to be regarded as biosimilar. As a result, comparative non-clinical and clinical data must be submitted. The clinical data to be submitted will be determined independently for each product.

Regarding manufacturing, the biosimilar product must have its own specific manufacturing process for both the active substance and drug product. The process should be developed and optimized taking into account state-of-the-art science and technology. Additionally, the manufacturer of a biosimilar product (both the active substance and drug product) should be approved by the JFDA according to the drug manufacturer accreditation criteria.

Regarding the analytical procedures, extensive, sensitive state-of-the-art analytical methods should be applied to maximize the potential for detecting small differences in all relevant quality attributes. If available, standards and internal reference materials (such as from the European Pharmacopeia and the WHO) should be used for qualification and validation.

Non-clinical requirements

Biosimilar products must undergo appropriate non-clinical testing (in vitro and in vivo studies) to justify conducting clinical studies. These studies should also be comparative with the reference product with the aim of detecting differences between the biosimilar product and the reference product. According to the JFDA, ongoing consideration should be given to the use of emerging technologies (such as real-time binding assays (for in vitro testing) and genomic/proteomic microarray science (for in vivo testing) to detect minor changes in biological response to pharmacologically active substances. In vitro studies should include receptor binding or cell-based assay studies. In vivo studies should include animal pharmacodynamics studies, at least one repeat-dose toxicity study and relevant safety observations. Other toxicological studies are not required unless warranted by the results from the repeated toxicological studies and/or based on the known properties of the reference product.

Clinical Studies

Comparative pharmacokinetic studies should be conducted to demonstrate the similarities in the pharmacokinetic (PK) characteristics between the biosimilar and the reference product. Healthy volunteers can be used for such comparative PK studies. The choice of design of these studies must be justified and should consider factors such as clearance and terminal half-life, linearity of PK parameters, the endogenous level and diurnal variations of the protein under study (when applicable), production of neutralizing antibodies, the conditions and the disease to be treated as well as the route of administration. Additionally, based on the biosimilar product and its half-life, an appropriate pharmacokinetic design should be set. The acceptance range/equivalence margin to conclude clinical PK comparability should be defined prior to initiating a study, taking into consideration known PK parameters and their variations, assay methodologies, safety and efficacy of the reference product.

Pharmacodynamic (PD) studies should also be comparative in nature. The parameters studied should be clinical relevant or employ a clinically validated surrogate marker. The PD study may be combined with the PK study and the PK/PD relationship characterized.

Additionally, comparative PK/PD studies may be sufficient to demonstrate comparable clinical efficacy if the following are met:

  1. The PK and PK properties of the reference product are well characterized.
  2. Sufficient information regarding the PD parameters is available.
  3. At least one PD marker is accepted as a surrogate marker for efficacy.
  4. Dose response is sufficiently characterized.
  5. The equivalence margin is pre-defined and appropriately justified.
  6. The most sensitive population, dose and route of administration has been used.

Clinical efficacy trials

Comparative clinical trials are required to demonstrate the similarity in efficacy and safety profiles between the biosimilar and the reference product. The study population used should be representative of the approved therapeutic indication for the reference product and is sensitive to detect potential differences between the biosimilar and reference products. Equivalent, rather than non-inferior efficacy, should be demonstrated in order for the biosimilar product to adopt the posology of the reference product and to open the possibility of extrapolation to other indications, which may include different dosages.

The safety of a biosimilar should be demonstrated to be similar to that of the reference product in terms of the nature, seriousness and frequency of adverse events. Therefore, data from a sufficient number of patients and study duration with sufficient statistical power to detect major safety differences is required. A written rationale on the strategy for testing immunogenicity should be provided and state-of-the-art methods should be used.

Post-marketing risk management and pharmacovigilance plan and periodic safety update reports

A post-marketing risk management plan (RMP) is required and must include detailed information of a systematic testing plan for monitoring the immunogenicity of the biosimilar post-approval. The RMP must be maintained throughout the entire life-cycle of a product and include:

  1. Risk identification and characterization (for example, case definitions, antibody assays).
  2. Risk monitoring (for example, it must include a specific framework to associate risk with a biosimilar product).
  3. Risk minimization and mitigation strategies.
  4. Risk communication (for example, it should include mitigation messages for patients and physicians).
  5. Monitoring activities to ensure the effectiveness of risk minimization.
  6. Detailed information of a systemic evaluation of the immunogenicity of a biosimilar product.
  7. A discussion about methods to distinguish adverse event reports from those for other licensed products, including the reference product.

A pharmacovigilance plan must also be designed and implemented. The pharmacovigilance plan should be designed to monitor and detect both known inherent safety concerns as well as any unknown safety concerns that might result from the impurity profiles of a biosimilar product or may not have been detected in the pre-market testing or otherwise not expected. Additionally, the pharmacovigilance plan should be able to distinguish between the biosimilar and reference product and track different products and manufacturers in the same class. The purpose of this requirement is to help ensure that adverse events are properly attributed to the relevant medical product.

A periodic safety update report (PSUR) of a biosimilar product must also be submitted. This report must evaluate the benefit/risk of a biosimilar product post-marketing.

Interchangeability and substitution

The guideline makes clear that the decision to treat a new patient with either a biosimilar or reference product, or to switch a patient already being treated with a reference product to a biosimilar product, should only be done by a qualified health care professional. Moreover, the guideline states that automatic substitution of biologics with biosimilar products is not permitted.


The guideline states that all biosimilar products should be distinguishable by name. Specifically, each biosimilar product should have a brand name that is not suggestive of the originator’s name or other biosimilar products. Thus, every medicine will have either a trade name or the name of the active substance (such as the International Non-proprietary Name (INN)) together with a company name/trademark. According to the guideline, the approved name, batch number, country of origin and manufacturer will be important for clear identification of biological products in Jordan.

Please continue to watch the BRIC Wall Blog for updates on biosimilars in Jordan and throughout the rest of the world.

This post was written by Lisa Mueller.

Can the Minimum Period of 5 years Established by NAFTA for Regulatory Data Exclusivity be Extended in Mexico for Biological Medical Products?

In Mexico, there is no specific body of legislation governing data protection exclusivity (DPE), also known as regulatory exclusivity, for chemical drugs, biological medical products and new indications. The authority responsible for enforcing the regulatory framework for drugs, biological medical products and medical devices, is the Federal Commission for Protection against Sanitary Risks (COFEPRIS), which is part of the Ministry of Health.

In 2012, in an attempt to provide guidance on DPE, COFEPRIS issued internal guidelines that provided a 5 year-term of data protection for new chemical entities only. The guidelines did not address DPE for biological medical products and new indications. Moreover, the reliability and legal value of these guidelines remains uncertain. However, up to now, these internal guidelines have not been challenged or contested by any generic companies.

Based on the interpretation of international treaties (namely, NAFTA and TRIPS), along with the Mexican legislation specifically related to approval of new molecules, innovator companies have successfully obtained regulatory data exclusivity of 5 years through litigation for new chemical entities, formulations and new indications.

Regarding the length of DPE protection, NAFTA states that it should be for at least 5 years. However, for biological medical products, some countries such as United States, Canada, the European Union, among others, grant a greater length of protection of regulatory exclusivity. 

Article 222 bis of the Mexican General Health Law defines a “biologic product” as any substance that has been manufactured by molecular biotechnology; has therapeutic, preventive or rehabilitative effects; is provided in a dosage form; and is identified as such by its pharmacological activity and physical, chemical and biological properties.

At the end of 2012, Janssen Cilag (Janssen) requested DPE for a biological medical product. Based on an interpretation of International Treaties, International Comparative Law and Mexican regulations for biological medical product approval, protection beyond the minimum period of 5 years established by NAFTA was requested. This request was ignored by COFEPRIS, which was understood as a tacit negative response. As a result of this reaction, at the beginning of 2013, the tacit negative response was challenged before the Federal Court for Tax and Administrative Affairs (FCTA). On November 2014, the FCTA confirmed the denial to grant the protection holding that the minimum period of 5 years established by NAFTA had already expired. The FCTA also concluded that foreign legislation was neither applicable nor mandatory and that the plaintiff failed to prove that considerable efforts were involved in the generation of data and information to prove the safety and efficacy of the biological medical product.

As a result of an appeal, in June 2015, a Federal Circuit Court issued a decision ordering the lower FCTA court to issue a new, accurate decision on the merits, providing certain guidelines as to how to decide the time of protection for clinical data of a biological medical product. In a complying decision issued in July 2015, the FCTA concluded that Janssen had demonstrated that the generation of data and information aimed to prove the safety and efficacy for the biological medical product involved considerable efforts. The FCTA also concluded that COFEPRIS did not accurately analyze the case. As a result, at that point of time, FCTA was unable to assess the applicable provisions in NAFTA, which established a possibility of granting a longer period of protection than the minimum period of 5 years. For this reason, FCTA held that it could not act as an administrative authority. Therefore, it ordered COFEPRIS to issue an accurate decision determining whether to expressly recognize a longer period of protection than the minimum of 5 years established by NAFTA. The FCTA’s decision is awaiting further action by COFEPRIS.

This case is very important because for the first time ever the Mexican courts are contemplating the possibility of having the minimum period of 5 years established by NAFTA as a minimum period of protection and not the only established period of protection for clinical data.

This post was written by Lisa Mueller, Mauricio Sámano and Ingrid Ortiz of Olivares.

A Report from the “Biosimilars and Biotech: MENA Conference” in Istanbul, Turkey: Part 1

This is part 1 in a series reporting on the conference entitled, “Biosimilars and Biotech:  MENA Conference” sponsored by Informa in Istanbul, Turkey on November 18-19th. As mentioned in my post of November 17th, not only did I attend the conference but presented as well. I found the conference to contain a number of really exciting, interesting and useful presentations. In the next few posts, I will provide a summary of some of the presentations that I believe readers of the BRIC Wall Blog will find insightful, and hopefully useful. 

Biosimilar Development in the Middle East – A Report

A very interesting presentation was given by Dr. Claudia Palmer (Partner and Managing Director of 55east FZ LLC) on the development of biosimilars in the Middle East. Dr. Palmer started her presentation by discussing the exchange she frequently has when asking various stakeholders in the Middle East for their view on the biosimilar marketplace. The response she typically receives is: “Biosimilars? Do you have them?” Ms. Palmer stated that currently, because there are so few companies in the area dealing in biopharmaceuticals, very few biosimilars are actually available. 

Despite the limited number of biosimilars presently available, Ms. Palmer stated that the region holds substantial potential for the growth of these products. Specifically, she noted: (1) the population in the Middle East is more than 200 million and is among the fastest growing in the world; (2) there is now political and fiscal stability in the region; (3) the economies of many countries in the area are booming; (4) there is a growing middle class; (5) life styles are changing and life expectancy is increasing; (6) the incidences of serious disease is increasing; and (7) the quality healthcare is improving and the sophistication of treatment increasing. 

With respect to biologics, Ms. Palmer stated that the price tag that typically accompanies biologics (such as seen in the U.S.) simply is not viable for many of the smaller Middle Eastern countries. In fact, in her view, as the incidences of cancer grow in this area, biosimilars will be the only affordable treatments for these diseases in many of these countries. Interestingly, Ms. Palmer commented that no one is really sure the exact amount that can be saved by treating a patient with a biosimilar instead of with an innovator biologic. 

In Ms. Palmer’s view, there is an opportunity for early entry of three biosimilar products in the region. These products would be erythropoietin (EPO), somatotropin and filgrastim. Ms. Palmer believes that the market opportunity for these three drugs in the Middle East, Turkey and Africa (META) region would be around $160-$190 million dollars, about 3% of the total biosimilar market. She indicated that this number was small because the path to market for any biosimilars in the region was going to be challenging.   First, she noted that it generally takes about two to three years once a biologic is approved in the U.S. or Europe for that biologic to become accessible in the Middle East. Once the biologic becomes available in the region, adoption tends to be slower than in the rest of the world due to a lack of infrastructure and the lack of insurance coverage for these products. Additionally, further complicating matters is that a number of countries in the Middle East have not yet established biosimilar frameworks. As Ms. Palmer noted, a biosimilar is only a biosimilar if it has gone through a biosimilar pathway. 

Ms. Palmer also stated there will likely be issues with pricing and reimbursement for biosimilars in these countries. Specifically, she noted that tenders comprise a majority of the market (likely over 80%) and the systems are not always transparent. Moreover, in many instances, preference for tenders is given to local biopharmaceutical companies. 

With respect to potential customers, Ms. Palmer stated that the typical buying entities for speciality drugs in this region will likely include: Ministries of Health, central pharmacies, army/military, hospitals, non-governmental organizations (NGOs) and dialysis centers. Ms. Palmer noted that biologics treatment is normally provided in the region by hospitals and dialysis centers. For nationals receiving these treatments, the treatment is generally paid for by the national healthcare system or by insurance. 

Ms. Palmer noted that so far, competition for biosimilars in the region has been limited. Multinational generic companies such as Hospira and Sandoz seem to have the best regional footprint so far. She also noted that currently there are really no local manufacturers in the area to speak of. The lack of such local manufacturers presents a number of positives and negatives. In terms of positives, no local manufacturers means that there will be a longer lead time for local companies to enter the market. Moreover, the lack of local manufacturing might make it hard for authorities to insist on a preference for a local product (particularly if there is none). Finally, the lack local manufacturers might facilitate the slowing of price erosion. With respect to the negatives, the lack of competition will likely mean that there will be few to no companies to partner with for the purposes of contract manufacturing. This lack of manufacturers might cause a cojoining of manufacturers and distributors which might result in a skills gap that could create challenges in distribution. Additionally, the lack of local manufacturers might also impact the ultimate acceptance of these biosimilar products and might instead increase tolerance for products imported from India or China. 

Near the end of her presentation, Ms. Palmer stated that companies interested in entering the biosimilar market in the Middle East will need to enhance their capabilities across their organizations and value chains. Ms. Palmer stated that any such companies will want to first make sure they have obtained either a U.S. or European registration for their biosimilars. Next, companies will want to invest in stakeholder management. Specifically, companies will want to: (1) build a network of regional stakeholders; (2) create awareness among these stakeholders; and (3) educate and train these stakeholders. Moreover, when dealing with local regulatory organizations, companies will want to drive rapid marketing authorizations. Businesses will also need to adapt their value chain by: (1) building a tender infrastructure; (2) enhancing supply chain capability; (3) enabling distributors; and (4) engaging with local players. Finally, businesses will want to align the commercial organization by: (1) establishing a speciality marketing approach; (2) developing key account skills; (3) clarifying conflicts of interest; (4) customizing medical education; and (5) leveraging existing footprints. 

At the end of her presentation, Ms. Palmer concluded with the following: 

  1. In general, the Middle East and Africa are the final frontier in pharma: In Ms. Palmer’s view, this is the last sizable area of untapped growth having limited competition. 
  2. Biosimilars hold a big promise for the Middle East: Biosimilars will provide modern treatments for large populations with limited purchasing power. 
  3. The biosimilars market will have to be built: Companies will need to work heard to create awareness, education and a safe supply of drugs. 
  4. This will be a marathon, not a sprint: As discussed previously, the current META commercial opportunity is around $160-$190 million for EPO, filgrastim and somatotropin.
  5. Regulatory capability, market access and process management will drive success: The complexity of the challenge will be an opportunity for the right company. 
  6. The government will become your partner: According to Ms. Palmer, with tenders comprising 80% and more of the biosimilars market, stakeholder management and key account skills will be essential. 
  7. Build a biosimilars ecosystem:  Ms. Palmer noted that like a highly developed machine, biosimilar treatment can only thrive in a sophisticated, supportive environment. 

This post was written by Lisa Mueller.