Abstract

By 2020, it is predicted that the Biosimilar market globally will cross US$20 Billion. With an increasing number of patent expires and more clear regulation processes, Biosimilars have emerged as one of the fastest-growing categories in the biopharmaceutical sector. The increasing need for cost-effective treatment is one of the major factors driving this market's growth in the coming years. Biosimilars cost 10% to 30% lesser than their parent products which is one of the primary factors fueling their adoption. This article mainly focuses on what is Biosimilar, overview of regulation; products approved related to Biosimilar in USA, Europe & India and few challenges in patent researching and analysis related to Biosimilars.

Introduction to Biosimilar:

About Biological Products, Biosimilar and Interchangeable

Biological Products:

Biological products are made from living organisms. The material they are made from can come from many sources, including humans, animals and microorganisms such as bacteria or yeast. Biological products are manufactured through biotechnology, derived from natural sources or, in some cases, produced synthetically.

Many of today's important medications are biological products. Biological products are among the medications used to treat conditions such as rheumatoid arthritis, anemia, Alzheimer's disease, multiple sclerosis, low white blood cell counts, inflammatory bowel disease, skin conditions such as psoriasis, various forms of cancer and other serious diseases.

Types of Biological products are: blood and blood products, proteins, vaccines, allergenic extracts, human cells and tissues used for transplantation, gene and cellular therapies. [1] Table 1 lists the example of biological products with technology classification.

Table 1: Example of Biological Products

Biosimilar:

Biosimilars are a type of biological products that are approved by regulatory authorities because they are highly similar to an already approved biological product, known as the biological reference product and have been shown to have no clinically meaningful differences from the reference product. Minor differences in clinically inactive components are allowed, but there must be no clinically meaningful differences between the biosimilar and the reference product when it compared in terms of the safety, purity and potency of the product. [2, 3]

Interchangeable:

An Interchangeable biological product is biosimilar to the reference product that meets additional standards for interchangeability and is expected to produce the same clinical result as of the reference product in any given patient, and for a product that is given to a patient more than once, the risk in terms of safety and effectiveness of alternating or switching between the interchangeable and the reference product is not greater than the risk of using the reference product without alternating or switching. [2]

Why biosimilars are not considered as generic medicines?

A biosimilar is not regarded as a generic of a biological medicine. This is mostly because the natural variability and more complex manufacturing of biological medicines do not allow an exact replication of the molecular microheterogeneity. The generic drugs are copies of brand-name drugs, have the same active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. That means the brand-name and the generic are bioequivalent. Biosimilars are highly similar to the reference product they were compared to, but have allowable differences because they are made from living organisms. Biosimilars also have no clinically meaningful differences in terms of safety, purity, and potency from the reference product. [1, 4, 6]

Table 2: Comparison between Generics and biosimilars [1, 4, 5, 6]

Biosimilar in USA:

Biologics Price Competition and Innovation Act 2009

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) which is amendment to Public Health Service Act (PHS Act) creates an abbreviated licensure pathway for biological products that are demonstrated to be "biosimilar" to or "interchangeable" with an FDA-licensed biological product (42 U.S.C. §262(k)). [2]

As per 42 U.S.C. §262(k)(2) the manufacturers must submit a 351(k) biologics license application (BLA) that includes, among other things, information demonstrating biosimilarity based upon:

• Analytical studies demonstrating that the biological product is "highly similar" to the reference product notwithstanding minor differences in clinically inactive components
• Animal studies (including the assessment of toxicity)
• A clinical study or studies (including the assessment of immunogenicity and pharmacokinetics (PK) or pharmacodynamics (PD)) sufficient to demonstrate safety, purity, and potency in 1 or more appropriate conditions of use for which the reference product is licensed and for which licensure is sought for the biosimilar product. [2]

The BPCI Act (42 U.S.C. §262(k)(7)) provides reference biological drug products 12 years of marketing exclusivity for new "biological structures". If a biosimilar application is filed by the same manufacturer of the pioneer product (or a related party), the changed biological structure must also result in

• Change in indications, route of administration, dosing schedule, dosing form, delivery system, delivery device or strength
• Change in safety, purity or potency, new 12-year exclusivity period is to be awarded [2]

An application for Interchangeable can file after four years of biologic structure (12-year) exclusivity. [2]

Once the first interchangeable product has been approved, no subsequent interchangeable applications will be approved until one year after the first commercial marketing of interchangeable biosimilar biological product. This Timeline is extendable in case of litigation (42 U.S.C. §262(k)(6)). [2]

The pediatric exclusivity under the BPCI Act adds six months to 12-year exclusivity and six months to the four-year filing restriction (42 U.S.C. §262(m)(3)). [2]

As per 42 U.S.C. §262(i)(1) the Biosimilar applicant learns of the patents that protect the pioneer biologic only after providing the pioneer with confidential access to its application and related manufacturing process. The biosimilar applicant and pioneer then undertake a complex exchange of patent information (the "patent dance") over an approximate two-month period to compile a list of "agreed to" patents that will be subject to a "first wave" of pre-launch litigation. The pioneer then has 30 days to file suit on those patents to enjoin biosimilar launch or else only royalties can be obtained in subsequent litigation on those patents.

The U.S. Supreme Court on June 12, 2017 interpreted the BPCI Act such that the biosimilar patent dance is not mandatory in SANDOZ INC. v. AMGEN INC. ET AL. The Supreme Court decided that Applicant of Biosimilar did not violate the BPCI Act by failing to engage in the patent dance, as consequences for failure to do so are expressly stated in the BPCI Act - meaning that failure to participate was expressly contemplated by the BPCI Act. The Court explained that failing to disclose its application and manufacturing information as required under 42 U.S.C. §262 (l)(2)(A) does not constitute an act of artificial infringement, but is actionable under 42 U.S.C. §262 (l)(9)(C), which permits the sponsor to bring an immediate declaratory judgment action for artificial infringement. [7]

The BPCI Act also provides for a "second wave" of pre-launch litigation by requiring the biosimilar applicant to notify the pioneer a second time at least 180 days prior to launch. Patents that were disclosed, but not on the "agreed to" list during the first dance, are eligible for possible injunctive relief, and applicants can file Declaratory Judgments during this second wave on patents that the pioneer elects not to pursue (42 U.S.C. §262 (i)(8)). [2, 7]

Biosimilar Interchangeability:

The USFDA on January 17, 2017 released a draft guidance detailing the agency's expectations for demonstrating biosimilar interchangeability.

FDA proposed Biosimilar applicant should consider an array of factors ("totality of factors") when determining the type and amount of data to support a demonstration of interchangeability, including product complexity and product-specific immunogenicity risk.

According to FDA, switching studies should be designed to determine whether alternating between a biosimilar and its reference product two or more times impacts the safety or efficacy of the treatment course. However, if the product is only intended to be administered once, Biosimilar applicant may instead provide a justification for not needing to conduct a switching study.

FDA also says that Biosimilar applicant should carefully consider their product presentation, including the delivery device and container closure system, as differences in presentation may affect FDA's determination of interchangeability. Applicant should not try to get an interchangeable biosimilar approved with a different type of presentation than the reference product. [8]

The "Purple Book":

The "Purple Book" lists biological products, including any biosimilar and interchangeable biological products, licensed by FDA under the Public Health Service Act (the PHS Act).

The Purple Book includes the date a biological product was licensed and whether FDA evaluated the biological product for reference product exclusivity. The Purple Book, in addition to the date licensed, also includes whether a biological product has been determined by FDA to be biosimilar to or interchangeable with a reference biological product (an already-licensed FDA biological product) [9]

Biosimilars Approved in USA:

Table 3: Biosimilars approved in USA [10]

Biosimilar in Europe:

Legislation Directive 2001/83/EC

The EU has pioneered the regulation of biosimilars since the approval of the first one (the growth hormone somatropin) in 2006 with legislation Directive 2001/83/EC, as amended (2004/27/EC) in March 2004: Article 10.4. [11]

Since biosimilars are a type of biological medicine, all features pertinent to biological medicines apply.

The biosimilar has physical, chemical and biological properties highly similar to that of the reference medicines. There may be minor differences from the reference medicine which are not clinically meaningful in terms of safety or efficacy. Minor variability is only allowed when scientific evidence shows that it does not affect the safety and efficacy of the biosimilar. The range of variability allowed for a biosimilar is the same as that allowed between batches of the reference medicine. This is achieved with a robust manufacturing process to ensure that all batches of the medicine are of proven quality. [4]

The exclusivity period provision in Europe is the same for both biologics and chemical drugs. All medicines produced using biotechnology and those for specific indications (e.g. for cancer, neurodegeneration and auto-immune diseases) must be approved in the EU through EMA (European Medicines Agency) also known as 'centralized procedure'. Nearly all biosimilars approved for use in the EU have been approved centrally, as they use biotechnology for their production. Some biosimilars may be approved at national level, such as some low-molecular weight heparins derived from porcine intestinal mucosa. [4]

When a company applies for marketing authorization at EMA, data are evaluated by EMA's scientific committees on human medicines and on safety (the CHMP and PRAC), as well as by EU experts on biological medicines (Biologics Working Party) and specialists in biosimilars (Biosimilar Working Party). The review by EMA results in a scientific opinion, which is then sent to the European Commission, which ultimately grants an EU-wide marketing authorization. Image 1 depicts steps of Biosimilar development.[4]

Image 1: Biosimilar Development in steps [4]

Biosimilar Interchangeability:

The terminology to refer to interchangeability and substitution practices in the EU:

Interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one biosimilar with another. Replacement can be done by:

• Switching (Physician Decision) - the prescriber decides to exchange one medicine for another medicine with the same therapeutic intent.
• Substitution (automatic) (Pharmacist action) - practice of dispensing one medicine instead of another equivalent and interchangeable medicine at pharmacy level without consulting the prescriber.

As per provision EMA carries out the scientific review of a biosimilar, the evaluations do not include recommendations on whether the biosimilar is interchangeable with the reference medicine, and thus whether the reference medicine can be switched or substituted with the biosimilar. The decision on whether to allow interchangeable use and substitution of the reference biological medicine and the biosimilar is taken at national level. [4]

There is convergence across EU countries that biologic medicines should not be substituted at the pharmacy level without the involvement of the clinical decision maker. [13] Image 2 provides switching policy in Biosimilars.

Image 2: Biosimilars switching policy [4]

Biosimilars Approved in Europe:

More than 25 biosimilars are approved in EU. Few of them are listed in Table 4 below:

Table 4: Biosimilars approved in Europe [14]

Biosimilar in India:

CSIR Guidelines:

The Central Drugs Standard Control Organization is the national regulatory body of India released new guideline for biosimilars which is effective from August 15, 2016. The new guideline is a slight change of the previous Biosimilars guideline "Draft Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India" released in 2012. The 2012 Guideline on similar biologics address the pre-marketing and post-marketing regulatory requirement (i.e. "comparability exercise"), and also address the requirements related to manufacturing process and quality control. [15]

India has adopted a "sequential approach" (like "stepwise approach" - US and EU) to market biosimilar products. The 2016 guidelines focus more on Post marketing. The major change mentioned in new guideline is the Reference product. If the reference product is not marketed in India, it can be licensed in any ICH country. [16]

Biosimilars Approved in India:

More than 25 biosimilars are approved in India. Few of them are listed in Table 5 below:

Table 5: Biosimilars approved in India [17]

Patent Research & Analytics Challenges for Biosimilars:

Patent research and analytics of Biosimilars is challenging and time-consuming because of

• Complex structure and function of Biological molecules
• Various keywords for same biological molecule like brand name, generic name, keywords based on target site, keywords based on mode of action, acronyms, abbreviations, spelling variations and truncations, etc.
  • For example: For Adalimumab, Keywords can be Adalimumab, Humira, Trudexa, Amjevita, humanized monoclonal antibody, human monoclonal antibody, anti-TNF mAb, anti-TNF monoclonal antibodie, D2E7 Heavy chain, D2E7 Light chain, TNF-α, TNF-alpha, hTNFα, hTNF, TNFA, TNFSF2, etc.
• Like Chemical Structure search in chemical molecules, Sequence search (Nucleotide and Protein) in Biosimilars is key and universal approach. Not only 100% match sequence is relevant as chances are there that part of entire sequence is claimed. Difficulties of determining fragment of sequence considered as relevant
• Multiple assignees work on same Biosimilar and file patent applications. You need to be very careful in collecting patent documents of all assignees considering in mind complete corporate hierarchy of companies.
• Companies developing Biosimilars tend to file patent applications vigorously. One patent family could be large to contain hundreds of patents and applications. The family is having patent documents related to Biosimilar as well as all its possible variations. Hence challenge is to isolate patent documents which are relevant for Biosimilar of our interest.
  • For Example, a patent family of US6090382 covering Humira (Adalimumab) assigned to BASF contains 129 publications (INPADOC family members)
• Apart from product patent covering Biosimilar, we must take care of patents claiming composition, Process of manufacturing / screening / purification / characterization, method of use, etc. You must need to see expiry of all these.
  • For example, For Adalimumab (Humira), product patent covering Adalimumab expired in end of 2016, but still more than 70 patents are alive wherein 14 patents are on Humira Formulation, more than 20 patents on method of manufacturing and more than 20 patents on method of treatment.

References: