BIOAVAILABILITY AND BIOEQUIVALENCE OF BIOSIMILARS

BIOAVAILABILITY AND BIOEQUIVALENCE OF BIOSIMILARS

Aanchal Arora ^{* 1} and Amrita Parle ²

Department of Quality Assurance ¹, Department of Pharmaceutical Chemistry ², Delhi Institute of Pharmaceutical Sciences and Research, Sector-3, Pushp Vihar, M. B. Road, New Delhi - 110017, India.

ABSTRACT: Biosimilars are the most promising medicines for treating complex diseases. The first biosimilar was approved in India in 2000, and since then, there is no looking back. CDSCO in collaboration with DBT has developed new guidelines in 2012, which were revised in 2016 for pre and post-marketing approval of biosimilars in India. India is one of the leading manufacturers of biosimilars catering to domestic and international market. Soon it will have a vast opportunity to develop more similar biologics as the patent of many biologics is scheduled to expire by the year 2020. India has emerged well in global market of biosimilars. India started its journey with near about US$ 250 million biosimilar market in 2015 and it is estimated to reach around  US$ 40 billion in India while US$ 240 billion in world by 2030. Biosimilars are the boon in treating patients.

Biosimilars, Biologics, Interchangeability, Bioavailability, Bioequivalence

INTRODUCTION: Biosimilars are the products that are extremely similar to an already existing original biologic, which can be an innovator or brand name product. But unlike a generic product, they are not identical. Biologics are highly effective and very specific medicines made by living cells. These are used to improve health in complex conditions like diabetes, cancer, growth deficiencies etc. Few examples of biologics include hormones, vaccines, growth factors, blood products etc. Biologics are delivered to patients through injections either by subcutaneous or intravenous route. Biologics cannot be administered orally as they become ineffective during the process of digestion. Biosimilar is a biologic product, which is very similar to approved biological product known as reference product with no clinically significant differences in terms of safety and efficacy ¹.  The aim of biosimilar development is to demonstrate biosimilarity that is highly similar in terms of biological activity, structure, safety, efficacy, and immunogenic profile ².

Difference between Generics, Biologics and Biosimilars:

Generics: Generic medication is created similar to an already marketed brand name in dosage form, safety, strength, route of administration, quality, performance characteristics, and intended use. Once the patent expires, other companies can reproduce the same active pharmaceutical ingredient as the original product. After approval from the regulatory bodies like FDA, they can sell this product into the market as a generic product. The innovator product and the generic products are considered to be bioequivalent due to the same API ³.

Biologics: These are very large and complex molecular structures. These are produced by living cells through complex biotechnological processes using highly specialized ingredients ². Biological products include a wide range of products such as vaccines, blood & blood components, allergenic, somatic cells, tissues, and recombinant therapeutic proteins ⁴. Biologics are currently preferred specialized products useful in treating critical illnesses, but the major drawback of high cost makes them unaffordable to many patients, especially in developing countries ⁵.

Biosimilars: A biosimilar or similar biologic can be defined as a biological product that is formed by genetic engineering techniques and is “similar” in terms of safety, efficacy, and quality to the reference biologic ⁶ but available at a much lower cost. There are inherent variations from batch to batch of a biologic; these changes are secondary and tightly controlled by the manufacturing process within a definite range, so quality is not affected. This is not the same as the differences between the biologic and biosimilar. Because the cell cultures (starting material) and production steps are the exclusive knowledge of the originator, it is not possible for a biosimilar company to accurately replicate the original manufacturing process ⁷. It is believed that biosimilars will have a positive impact on drug pricing. This will reduce the overall cost of treatment and enhance accessibility to these life-saving drugs ⁸. A research study in the United States of America predicted that over the upcoming ten years, replacing biologics by biosimilars would reduce the cost burden by 54 billion US dollars ¹.

The biosimilar must have the same mechanisms of action, routes of administration, dosage forms, strengths and indications as that of reference drug ⁹.

Comparison of Biologic, Biosimilar and Generic Drugs:

Status/History: Europe was the first in the world to lay down the guidelines for the approval of biological products ¹⁰. In Europe, the first biologic - NUTROPIN AQ was approved in 2001, manufactured by Ipsen’s Pharma used for turner’s syndrome, long-term kidney disorders, and as growth hormone. Later in 2006, Sandoz-Novartis got approval for first biosimilar in Europe named OMNITROPE by Europe Medicinal Agency (EMA) ^{11, 12}. In 1991, United States got its first biologic - filgrastim manufactured by Neupogem used as a granulocyte agent approved by USFDA. The biosimilar of filgrastim was approved in 2015 named filgrastim-sndz manufactured by Sandoz-Novartis ⁹. Afterward, USFDA approved a number of biosimilars till date for the treatment of cancer and many other conditions.

Indian System: ‘Similar biologics’ is the term used by Indian regulatory agencies for biosimilar. Indian companies are taking numerous steps to get involved in global biosimilar market. India got its first biosimilar Biovac-B approved in 2000 and marketed by Wockhardt for hepatitis B although no guidelines were present at that time, it did not get credit of being first ¹³. More than 100 Indian biopharmaceutical companies are engaged in the manufacturing and marketing of biosimilars. India has a very flourishing biosmiliar domain in comparison to other countries as Indian Pharmaceutical companies are growing and glowing worldwide.

The approval process of biosimilar requires more data than generic drugs. To address the challenges associated with the development of biosimilars, Central Drugs Standard Control Organization (CDSCO) collaborated with the Department of Biotechnology (DBT) to form the guidelines for the manufacturing, approval and marketing of biosimilars in 2012 and revised them in 2016.

These guidelines address the regulatory requirements, principles for the development of biosimilars, data requirements for preclinical studies, clinical trials application, marketing authorization application and post-marketing surveillance for biosimilars ¹⁴. Principles for the development of biosimilars include the selection of reference biologics, proper manufacturing process and quality comparability studies of biosimilars.

FIG. 1: FACTORS PROMOTING GROWTH OF BIOSIMILAR MARKET

These guidelines also focus upon the regulations related to the quality, efficacy, and safety of biosimilars. CDSCO brought some major changes in its 2012 guidance which is revised in 2016 like [a] Now biologics can be approved either in India or any other international council for harmonization countries (i.e., European Union, Japan, United States, Canada, and Switzerland) but earlier it was important for the reference biologic to be approved in India for manufacturing of its biosimilar in India. It is also align with other international agencies like EMA and WHO. [b] Emphasis on post-marketing studies, CDSCO says, to further reduce the residual risk of biosimilar, phase IV studies must be conducted on minimum 200 patients within 2 years of getting the marketing approval ¹⁴.

Switching and Interchangeability: If a patient has a small molecule medication in his prescription, then a pharmacist have the right to substitute a generic version without consulting to the patient’s Physician, this is known as interchangeability. Whereas, biosimilars are not interchangeable with the original biologic. Physicians may switch the medication from original biologic to the biosimilar for the economic benefit of patients using available clinical evidence during a consultation. One-time switch of original biologic to biosimilar or reverse is known as switching. This process is reversible if the desired effect with substituted biosimilar is not observed. The switching should be made by the patient during consulting with the physician by using the available clinical evidence ¹⁵.

FIG. 2: IMMUNE RESPONSE AGAINST THERAPEUTIC PROTEINS

Immunogenicity: Therapeutic proteins are recognized by the human immune system. Immunogenicity refers to the ability of a drug to induce an immune response in the body. This potentially harmful immune response is complex and, in addition to ADA (Anti-Drug Antibodies) formation, involves T cell activation and innate immune responses ¹⁵. As biosimilars are proteins, they may induce immunogenic reactions in the body. Many patients, disease, and product-related factors may influence the immunogenicity of therapeutic proteins The possibility of these reactions must be discussed before starting the therapy and switching from original biologic to biosimilar or reverse.

Bioavailability: Bioavailability of a drug is defined as the extent and rate to which the active drug ingredient from the drug product is absorbed and becomes available at the site of drug action ¹⁶. Any alteration in the bioavailability of a drug is reflected in its pharmacological effects. The rate and extent of drug absorption are commonly measured by the maximum concentration (C_max) and area under the blood or plasma concentration-time curve (AUC). A slower rate of absorption is desired when the aim is to prolong the duration of action or to avoid the side effects. A comparative bioavailability study refers to the comparison of bioavailabilities of different formulations of the same drug or different drug products ¹⁷.

Fig. 3 shows that bioavailability depends upon 3 factors -

FIG. 3: FACTORS AFFECTING BIOAVAILABILITY

The bioavailability through the parenteral route is maximum as this route bypasses various metabolic processes. The dose available at the site of action is called the bioavailable dose or systemic availability. Bioavailability of drugs depends upon the route of administration. The bioavailability as per route of administration can be -

Parenteral > Oral > Rectal > Topical

The term bioavailable fraction (F), refers to the fraction of administered dose that enters the systemic circulation¹⁸.

F = Bioavailable dose / Administered dose

Bioequivalence: This term denotes that the drug substance in two or more identical dosage forms reaches the systemic circulation at the same relative rate and to the same relative extent, i.e., their plasma concentration-time profiles will be identical without significant statistical differences.

Bio-inequivalence: When statistically significant differences are observed in the bioavailability of two or more drug products ¹⁸.

Generic molecule before approval by FDA needs to prove bioequivalence by pharmacokinetic para-meters such as area under plasma-concentration time curve (AUC) and peak concentration (C_max) which can be provided through bioequivalence studies.

Types of Bioequivalence Studies -

1. In-vivo bioequivalence studies
2. In-vitro bioequivalence studies

The purpose of establishing bioequivalence is to demonstrate equivalence in quality between the proposed and existing drug product (e.g., generic versus brand, post-change versus pre-change product). Therefore, bioequivalence testing typically eliminates the need for preclinical tests and clinical trials.

Table 1 - 5 threw light on the status of biologics and biosimilars discovered and launched in INDIA, CANADA, JAPAN, the USA, and EUROPE from 2014-2019. All these biosimilars are approved by respective regulatory authorities like USFDA after proving the bioequivalence and toxicity studies.

Table 1- India: Central Drugs Standard Control Organization (CDSCO) and Food and Drug Administration (FDA) are the drug regulatory bodies of India. In 2012, the guidelines were made by CDSCO in collaboration with the Department of Biotechnology (DBT). According to the guidelines, it was essential that the reference biologic must be approved in India for manufacturing of its biosimilar in India. But these guidelines were further revised in 2016, which state that for manufacturing the biosimilars in India, the biologics can be approved either in India or in any country included in International Council for Harmonization (i.e., European Union, Japan, United States, Canada, and Switzerland) ¹⁴. Table 1 elaborates the bioavailability, product name, company, year of approval, prices, and therapeutic uses of biologics and biosimilars marketed in India in the span of five years from 2014 to 2019.

Table 2- Canada: Health Canada is a drug regulatory body of Canada. As per Health Canada, biosimilar can enter the market after the expiry of the reference biologic drug's patents and data protection. Health Canada authorizes biosimilars for sale using the same rigorous regulatory standards of quality, efficacy and safety adopted for biologic drugs ¹⁵. Table 2 elaborates the biovailability, product name, company, year of approval and therapeutic uses of biologics and biosimilars marketed in Canada in the span of five years from 2014 to 2019.

Table 3- Japan: Ministry of Health, Labor and Welfare (MHLW) is a healthcare regulatory body of Japan. The Japanese guideline states that for the development of a biosimilar product, a reference product must be approved in Japan and a single reference product should be used during the development of the biosimilar product ³⁹. Table 3 elaborates the biovailability, product name, company, year of approval and therapeutic uses of biologics and biosimilars marketed in Japan in the span of five years from 2014 to 2019.

Table 4- USA: United States Food and Drug Administration (USFDA) is the regulatory body of United States of America. It is the requirement of the USFDA that a manufacturer has to demonstrate the equivalence of the biosimilar with the reference biologic by characterizing the structure and establishing the efficacy. The tests such as purity, chemical identity, and bioactivity are performed to prove the similarity between the biosimilar and reference product. Minor differences like change in buffer or stabilizer between reference product and biosimilar are acceptable if they are not interfering in biological activity ⁴⁷. Table 4 elaborates the biovailability, product name, company, year of approval and therapeutic uses of biologics and biosimilars marketed in USA in the span of five years from 2014 to 2019.

Table 5- Europe: A biosimilar is a biological medicine highly similar to another already approved biological medicine (the 'reference medicine'). Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines. The European Medicines Agency (EMA) is responsible for evaluating the majority of applications to market biosimilars in the European Union (EU) ⁴⁹. Table 5 elaborates the bio-vailability, product name, company, year of approval and therapeutic uses of biologics and biosimilars marketed in Europe in the span of five years from 2014 to 2019.

Facts and Figures of Biosimilars and its Future: India got its first biosimilar approval in 2000. Indian biosimilar market catering to domestic population was about US $250 million, and export to other countries was about US $50 million in 2015. The compound annual growth rate was about 14% ¹. With the support of legislation and the Indian Government, the Indian biosimilar market continued to grow and reached a value of $2.2bn in 2017. India has strongly established itself in the global biosimilar market as well ⁵⁹. In 2018 Reliance Lifesciences topped the global pecking order, followed by Intas and Biocon. According to the Associated Chambers of Commerce of India’s 2017 report and based on the analysis of the currently approved biologic drugs, drugs in clinical pipeline, expectations around price erosion, and market penetration, 'Assocham and Sathguru' estimated that the global market for biosimilars would be about $240 billion by 2030 and the Indian domestic market could be about $40 billion ^{60, 61}. The above facts and the figures exhibit that the biosimilar market would grow multifold in a span of about 10 years. The future of biosimilars is bright, and it is expected to enter the mainstream of therapy.

TABLE 1: BIOLOGICS WITH BIOSIMILARS APPROVED IN INDIA FROM 2014-19 ^19-33

TABLE 2: BIOLOGICS AND BIOSIMILARS APPROVED IN CANADA FROM 2014-19 ^34-38

TABLE 3: BIOLOGICS AND BIOSIMILARS APPROVED IN JAPAN FROM 2014-19 ^40-46

TABLE 4: BIOLOGICS AND BIOSIMILARS APPROVED IN USA FROM 2014-19 ⁴⁸

TABLE 5: BIOLOGICS AND BIOSIMILARS APPROVED IN EUROPE FROM 2014-19 ^50-58

CONCLUSION: Biosimilars are the low-cost, highly effective, genetically engineered versions of biologics used for treating complex diseases like diabetes and cancer. Biosimilars are the order of the day all over the world and are developing at a fast pace to ensure high efficacy with clinical safety while treating complex disorders. Governments all over the world are supporting them for the benefit of mankind.

ACKNOWLEDGEMENT: Nil

CONFLICTS OF INTEREST: There is no conflict of interest.

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