Perspective, perceptions, and promulgation of biosimilars: A questionnaire-based study to assess and understand the current challenges of biosimilars to the potential and intended users

INTRODUCTION Biological products are defined as substances of biological origin that are assayed by biological tests and used in the prophylaxis, therapy, or diagnosis of human diseases (Reference: World Health Organization Technical Report Series [WHO TRS] 963). Various types of biological products include vaccine (a biological preparation that improves immunity to a particular disease, e.g., polio vaccine, Bacillus Calmette–Guérin (BCG), diphtheria-pertussis-tetanus (DPT), and hepatitis B), recombinant deoxyribonucleic acid (r-DNA)-based drugs (combination of two r-DNA strands artificially from two different sources to produce bio therapeutically active recombinant proteins, e.g., adalimumab and rituximab), blood, and blood products (obtained from pooled plasma of blood by fractionation, drawn from donors, e.g., coagulation factor VIII, human albumin, and prothrombin).[12] All vaccines and r-DNA products are new drugs under Rule 122-E and also vide G.S.R. 45(E) dated January 24, 2011.[3] The biosimiliars can be imported (Rule 122-A) and also can be manufactured (Rule 122-B) as per Drugs and Cosmetics Act 1940 & Rule 1945.[2] Process of approval/testing before the products are released in the market is as follows: (1) Clinical trial application in Form 44 along with common technical document module[4] and other related documents is submitted to the Central Drugs Standard Control Organisation (CDSCO) on SUGAM portal[4] for evaluation. (2) After satisfactory review of the application, the proposal may be referred to subject expert committee (SEC) for evaluation and subsequently to the technical committee for further deliberation. (3) On receipt of recommendations from both the committees, the clinical trial permission is granted to the firm. In the case of new chemical entities (NCE), the proposal may be referred to investigational new drug committee followed by technical committee and Apex committee for recommendation and further action. (4) On the basis of evaluation, the firm may be granted the permission to go for further trials or the permission to import/manufacture and market the new drug; in addition, in the case of vaccines, a parallel review of Chemistry, Manufacturing and Controls (CMC) is performed by Central Drugs Laboratory (CDL), Kasauli and the permission to import/manufacture and market the vaccine is granted on receipt of no objection certificate from CDL, Kasauli. The Guidelines on Similar Biologics was prepared by CDSCO and Department of Biotechnology (DBT) laid down the regulatory pathway for similar biologic claiming to be similar to an already-authorized reference biologic, which have come into effect from September 2012 [Table 1]. The revision of the 2012 DBT-CDSCO guidance document for the development and approval of Similar Biologics took place and the “Guidelines on Similar Biologics: Regulatory Requirements for Market Authorization in India 2016”[56] are now effective.Table 1: Various stakeholders involved in decision making of biosimilarsAs per Biosimilar guidelines, Similar biologics can only be developed against an authorized reference biologic that has been approved using a complete data package in India. In case, Reference biologic is not authorized in India, it should have been licensed in any international council for harmonization countries. The reference biologic product can be imported for developing the Similar biologic for quality, preclinical, and clinical comparability. The dosage form, strength, and route of administration of the similar biologic should be the same as that of reference biologic. Any product can be considered as Similar Biologic only if it is proven to be similar using extensive quality characterization against reference biologic product. Quality-based consideration for Similar Biologics includes the following: analytical methods; product characterization, specifications, stability, quality comparability study by quality attributes, which are divided into two categories––critical quality attributes and key quality attributes. It is important to establish a formal Risk Management Plan to monitor and detect both known inherent safety concerns and potential unknown safety signals that may arise from the Similar Biologic.[7] To further reduce the residual risk of the Similar Biologics, additional safety data may need to be collected after market approval through a predefined single-arm study of generally more than 200 evaluable patients and compared to historical data of the reference biologics. The study should be completed preferably within 2 years of market authorization/license. The primary aim of the post-marketing phase-IV study is safety and the secondary aim is efficacy and immunogenicity Due to increase in competition among the pharmaceutical companies, new products that are cheaper are introduced in the market every now and then.[8] Biological products, which are less expensive and show similar function to the original product, called the biosimilars, are ruling the pharmaceutical market. Biosimilars show similar effect as the parent or original biological product but it is not necessarily made up of same active ingredient or chemicals. Once the patent of the original biological product or biologic expires, it is legal for other pharmaceutical companies to manufacture the drug.[9] Therefore, it is impossible for a biosimilars to be the exact identical of the original product and thus they cannot be compared to generic drugs.[10] Biosimilars are estimated to be the top upcoming product in the field of medicines. Biosimilar drugs promise treatment of diseases such as cancer, HIV/AIDS, rheumatoid arthritis, and inflammatory bowel diseases. They are not only up to the mark in treating the patients but are also becoming the primary choice in the market due to their cheaper rate than the original product. As biosimilars are the replicas of the reference product, they require approvals along with successful clinical trials that assure the product’s quality, safety, and efficacy. Despite the several inherited advantages with the biosimilars, in India these are nascent phase because of several warming and warming challenges.[1112] The following study had been undertaken to the issues and challenges faced by industry and regulators with their potential solutions and recommendations [Table 2].Table 2: Perspective about biosimilarMATERIAL AND METHODS It was a cross-sectional questionnaire-based study carried out among various stakeholders including researchers, regulators, and industry people. Two hundred and seventy-five stakeholders participated in this study. The questionnaire was designed and tested among small groups for conducting a pilot study. Modified questionnaire was given to all participants. The questionnaire having 21 important questions/comments was given to participants after explaining the purpose of the study. Any doubts regarding questionnaire were clarified by the investigators. 30min was given for filling the questionnaire. The response in terms of responders vs. nonresponders, agree vs. disagree, and yes vs. no was recorded and analyzed by descriptive statistics using Microsoft Excel. RESULTS AND DISCUSSION The European Medicine Agency (EMA)[12] was the first regulatory body to publish guidelines on specific regulatory pathway for the approval of biosimilars in 2005.[10] These guidelines were titled as “Guidelines on similar biological medicinal products” and with time have they have been updated and improvised according to the requirements. However in India, guidelines for biosimilars have been published in 2012 as given in Table 3.Table 3: Status and regulatory authority for biosimilars: a comparison[10 11 12 13 14 15 16]Approximately 27.3% people are aware of the biosimilars [Figure 1]. In addition, the potential beneficiaries, that is, patients, also have poor awareness (18.2%). A large section of people (72.7%) need proper awareness [Figures 2 and 3]; the same can be achieved through awareness program.Figure 1: Awareness of biosimiliars Vs generics among the stakeholders and patientsFigure 2: Awareness of biosimilars among the stakeholders and patientsFigure 3: Stakeholders’ perception for biosimilars entry into IndiaIndia has also introduced regulations as per majority of countries including USA, UK, Japan, Singapore, and Canada, later in 2012. The majority of stakeholders (76.4%) in opinion that entry of biosimilar is a welcome step from government and same can be considered as a boon for the patients undergoing life-threatening diseases [Figure 4].Figure 4: General perception of stakeholders for biosimilarsThere is no doubt that biosimilar enhances the life span of patients (agreed by 69.1%). However, 83.6% stakeholders disagree that it can be better option from innovator product [Figure 5].Figure 5: Responses of various stakeholders against important issues of biosimilarsThe study shows the limitation regarding the qualified personnel involved in biosimilars, as approximately 91% people believe that there is lack of expertise in this field. The same can be achieved through government initiatives for bridge courses, which is also strongly felt by the major (83.6%) stakeholders who participated in the study. Another important concern raised by participants was the affordability and pricing. There is no proper regulation for the pricing and market access. Also biosimilars are compared with approved product rather than innovator products that affect the quality. However, industry has further limitation of timeline of the product access to the market. Considering the data generation as per need of regulators is uphill task for industry. Industry also raises the concern for single-window approval system of biosimilars. As government giving export incentives in varied products, industry is advocating similar incentive to support the production and export of biosimilars. CONCLUSIONS AND RECOMMENDATIONS Biosimilars show immense hope in the field of medicine because of their potential use and low cost than their original biologics. Although there are many countries that have not approved the use of biosimilars, there are few countries that have issued regulatory guidelines for biosimilars but hesitate to accept in using them. Their nonacceptance is due to very low knowledge of the biosimilars. This issue can be resolved by initiating new schemes that could educate patients and distributors about the efficacy and safety of the biosimilar. Different countries have issued different set of guidelines with no common regulation worldwide. Countries should work toward setting a new common set of guidelines for the easy flow of trade. This would allow a uniform harmonization of a biosimilar and their easy acceptance in different countries, which would further help in fast treatment of a disease and easy availability and accessibility of the medicine to the patients. Following needed to be taken into consideration for improving perceptions: enhance the perspective usage of biosimilar through promulgation and implementation of rules and regulation for all the stakeholders; educate patients and professionals’ about biosimilars; make better marketing and pricing policies to ensure benefits to the manufactures and patients; and assess patients’ indifferent geographical locations through patent studies. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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