Biologics are biotechnology-derived medicinal products manufactured from living organisms or contain components of living organisms, and these products are specifically designed to resemble the body proteins or modulate the immune system. Biological products have made a major transformation in the therapeutics of many diseases, particularly for chronic diseases involving overactive immune system or impaired immune surveillance12. A plethora of biological agents are currently available in the market, including insulins, vaccines, human growth hormone, erythropoietin, interleukins, interferon, clotting factors and monoclonal antibodies34. Biologic agents have shown greater clinical benefits as compared to conventional drugs1; however, the affordability of these medications is beyond many, which limits access especially in resource-limited countries. The increase in demand for cost-effective treatment, expiry of patents and marketing exclusivities of biologics have led to the development of biosimilars - biological agents that are similar to the innovator or previously licensed biologics (also known as reference product or reference biotherapeutic product; Fig. 1). The biosimilars are approved by the regulatory authorities based on rigorous comparative analytical, immunogenicity, non-clinical and clinical evaluations56. This article provides an overview of the approval process and the key attributes of the 2016 Indian Regulatory Guidelines for the approval of similar biologics. It also describes the unaddressed aspects such as interchangeability, nomenclature and labelling of similar biologics in India.
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Fig. 1: Classification of biopharmaceutical agents.
Definition of biosimilars
In India, biosimilars are known as similar biologics. According to the Central Drugs Standard Control Organization (CDSCO) and Department of Biotechnology (DBT) guidelines released in 2016, a similar biologic product is that which is similar in terms of quality, safety and efficacy to an approved reference biological product based on comparability7. Various countries and agencies follow different definition and terminology for biosimilars (Table)8910.
Table: Comparison of different regulatory guidelines for the approval of biosimilars
Intended copies
Intended copies (otherwise called as biomimics, me-too biologics, non-comparable biologics; Fig. 1), although claimed to be similar to original biologics, should be distinguished from biosimilars to avoid confusion. These biocopies do not undergo demonstration of similarity or lack comparative studies with appropriate reference product or did not achieve regulatory approval as per the regulatory requirement for biosimilars11. These biologics are often developed and marketed in various middle- and low-income countries having less robust regulatory requirements12. Patients administered with such biological agents face a greater risk of therapeutic failure and side effects. A study showed that the use of intended copies of etanercept and rituximab marketed in Columbia and Mexico resulted in failure to treatment and increased adverse events13. In Mexico, the intended copy of rituximab was withdrawn by Comisión Federal para la Protección Contra Riesgos Sanitarios due to the development of anaphylactic reactions in several patients who switched from the original product14.
Biobetters
Biobetters (also referred as biosuperiors, second- or next-generation biologics; Fig. 1) are different from biosimilars and are enhanced over the original product15. The original biologics are modified by either chemical (polyethylene glycol) or molecular (using recombinant DNA technology) method to develop these biobetters. These biologics may result in improved efficacy and reduced dosing frequency as well as safety risks such as immunogenicity, toxicity and adverse effects16. The regulatory approval of biobetters requires supporting evidence of efficacy and safety and is mostly eligible for patent protection17.
Biosimilars are not biogenerics
Unlike chemical generics, the development of biosimilars is unique and more complex in nature18. The chemical drugs are small molecule products that can be easily reproduced using chemical synthesis, as these have well-defined structure and formula. However, biosimilars are large molecules with multi-dimensional structure and are developed from cell lines or living organisms using recombinant DNA technology, which is more complicated compared to chemical synthesis1920. Further, manufacturing biosimilars such as monoclonal antibodies (molecular weight between 145,000 and 160,000 Da) is more intricate than biologics such as insulins and hormones (molecular weight of nearly 6000 Da; Fig. 2)212223.
Fig. 2: Comparison of small chemical drugs versus biologics.
The entire manufacturing process is performed under strictly controlled conditions, and it includes selection of the DNA sequence, cloning, transfection, amplification, purification, formulation and validation24 (Fig. 3). It remains a big challenge for a biosimilar manufacturing company to develop a similar product, as detailed information on the process of manufacturing of the original drug is patent protected and also because the same cell line is not available to the biosimilar manufacturer. Any changes in the manufacturing process such as use of different cell lines, growth medium and protein purification processes can also result in variations in the final product25. In addition, there are chances of batch-to-batch variations occurring for the same biosimilars and even for originator manufacturing the same biologic. These minor variations in biosimilars can be acceptable, but it is imperative to demonstrate that the variation due to the development process does not affect the products' physiochemical properties, effectiveness and quality26.
Fig. 3: Variation between manufacturing of biologics and similar biologics. The manufacturing process to produce biologics and similar biologics, include complex and controlled procedures. The process involves cloning of the relevant gene into a DNA vector and transferring it into a host cell. After the protein expression, appropriate cell line is selected and expanded in a growth medium using suitable expansion method. Complex purification and validation procedures are followed to obtain the purified final biological product. The characteristics of the final product may differ based on variation in selection of the DNA sequence, cloning, transfection, amplification, purification, formulation and validation procedure followed. rDNA, recombinant DNA.
Biosimilars: A potential for compromise
India, being one of the leading countries in manufacturing affordable, efficacious and safe generic medicines, has also emerged as a key player in biopharmaceuticals, especially in the manufacturing of biosimilars27. There are nearly 60 biological agents that have been approved in India and almost half of these are similar biologics28. The cost of biosimilars marketed in India is approximately half the cost of innovator products, and this difference is attributable to lower manufacturing and development cost. In addition, there are patient assistant programmes by manufacturing companies, which address the issues of affordability and access29. Although biosimilars have gained acceptance from both physicians and patients because of its affordable price, but there have been questions regarding their adequately similar efficacy and safety as compared with the reference product30. In controlled clinical studies of biologics, particularly biosimilars, safety concerns may occur beyond the study completion. Long-term evaluations such as post-marketing studies of biological agents are required as there are only limited patient experiences available during approval in terms of safety and immunogenicity. Side effects related to the long-term use, off-label use, drug-drug interactions or use in comorbid conditions can only be identified on exposure to the drug after its approval. Above all, as biological agents could lead to deviation in quality characteristics due to unknown variations (also known as drift) and known variations (evolution) in manufacturing process, it is important to establish long-term surveillance to prevent risk to patients31. It is also essential to improve the identifiability of the biologics after market approval with easily distinguishable product names32 and establish robust standards of interchangeability between two biological products to further improve the safety assessment31.
The assessment of toxicity and safety of monoclonal antibodies, in particular, is a cause of concern because of its increased complexity. The manufacturing of biosimilar monoclonal antibodies can cause disparities in glycosylation pattern, which could result in micro-heterogeneity. Development of guidance documents and assurance of similarity are daunting tasks with biologics such as monoclonal antibodies compared with other biologics. The World Health Organization (WHO) has drafted separate guidelines on evaluation of monoclonal antibodies as similar biotherapeutic products33.
Guidelines for similar biologics in India
In India, until July 2012, similar biologics were approved by Review Committee on Genetic Manipulation (RCGM) and CDSCO on a case-by-case basis using abbreviated pathway for new drugs34. The biological products launched in India until 2012 followed an ad hoc abbreviated procedure on a case-to-case basis, and these products underwent a necessary procedure as per the Indian guidelines to be categorized as true biosimilars34. As there was a growing trend in the development of biosimilars, and to improve the standards of the approval requirement at par with the established regulatory bodies such as European Medicines Agency (EMA) or the United States Food and Drug Administration (US FDA), the Indian regulatory agency considered providing a clear pathway enunciating the requirements to substantiate equivalence in safety, efficacy and quality of a similar biologic to an authorized reference biologic. The first 'Guidelines on Similar Biologics' framed by the CDSCO and DBT came into effect from September 201235. On August 15, 2016, the Indian Regulatory Authority released updated guidelines with several inputs from the WHO and expert consensus opinion7. The approval of biosimilars follows a sequential process and involves various authorities such as Institutional Biosafety Committees, Institutional Animal Ethics Committee, RCGM, Genetic Engineering Advisory Committee, Drug Controller General of India Office, and the Food and Drugs Control Administration336. These guidelines for similar biologics provide the regulatory requirements regarding manufacturing processes and quality aspects and comparative exercise for preclinical studies, clinical studies and post-marketing requirements. The guidance document recommends the use of reference biologic in all the comparability activity related to quality, preclinical and clinical considerations. The attributes of 2016 Indian Guidelines7 are compared with those of guidelines from established regulatory authorities, particularly US FDA8, EMA9, and WHO10Table I.
Reference biologic
The rationale for selecting the reference product should be provided to regulatory authorities and the reference product selected for the comparability exercise should be approved in India based on the complete data set7. The reference biologics that are not marketed in India ought to be licensed in any of the member countries of International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. The formulation, route of administration, dose and strength of similar biologics have to be similar to that of the reference product7.
Manufacturing process and quality considerations
The requirement of providing a complete description of the manufacturing process including biological raw materials used (such as host cell cultures, vectors and gene sequence) and post-translational modifications (e.g., glycosylation, oxidation, deamidation and phosphorylation) has been re-emphasized in the 2016 guidelines7. The description should include the comparability of product developed at clinical scale over reference biologic. Overall, the manufacturing process is required to be consistent and reproducible and should be in accordance with good manufacturing practices. The characterization studies for similar biologics should be performed to evaluate physicochemical properties, purity, content, strength, biological activity and immunogenicity. Stability studies along with accelerated studies and stress studies are required to be conducted for similar biologics for the evaluation of shelf life, storage conditions and degradation profile. Variances between the similar biologic and the reference product and their potential impact on the efficacy and safety of similar biologic should be investigated. For example, two candidate biosimilars of etanercept produced in China showed a difference in molecular mass, amino acid sequence and glycosylation pattern and therefore, did not meet the requirements of EMA to qualify as a biosimilar, although they exhibited affinity and biological activity analogous to those of the original product. This emphasizes the importance of exhibiting the similarity in the manufacturing process and the need for conducting preclinical and clinical studies to ensure standard efficacy and safety of the biosimilars3738.
Demonstration of similarity
In India, extensive characterization studies are recommended to determine the qualitative and quantitative difference between the candidate similar biologic and reference product7. The documentation should contain comprehensive information regarding the differences observed during analytical characterization, quality aspects and detection and estimation of relative levels of protein variants7. The pharmacokinetics (PK) study should be adequately powered to demonstrate equivalence in PK of similar biologic versus the reference product. The guidelines also recommend that PK and pharmacodynamic (PD) studies are to be conducted before the large-scale phase 3 studies. Thus, a sequential format for conducting these studies is important.
Preclinical and clinical studies
After the analytical evaluation that characterizes the similarity of similar biologic and reference biologic, preclinical and clinical studies are conducted to further evaluate the efficacy and safety aspects7. Evaluation of PD activity in vivo should be performed in case the in vitro studies (e.g., cell proliferation or receptor binding assays) do not reflect clinically relevant PD activity. A minimum of one repeat dose toxicity study (in vitro) in the relevant species should be performed7.
The guidelines require comparative PK and PD studies to establish the similarities in PK/PD characteristics between similar biologic and reference biologic on a case-to-case basis7. Both PD and PK studies may be combined, or PD study can also be conducted along with phase 3 studies wherever applicable. At least one randomized phase 3 study that is desirable to establish the similarity in efficacy and safety between the purported similar biologic and reference product, except recombinant human-soluble insulin products, where only comparison of safety is needed. Clinical studies having non-comparative safety and efficacy outcomes are generally not preferred, and it is desirable for all similar biologics to conduct equivalence (with predefined margins) or non-inferiority studies with adequate sample size (statistically determined based on the data from earlier PK/PD studies) and duration for demonstrating comparable safety, efficacy and immunogenicity with the reference biologic. If equivalence, non-inferiority or comparability studies are performed, the manufacturer must provides a clear justification and consult the CDSCO before initiating the study. Sample size estimation and its rationale and comparability limits have to be defined clearly and justified before initiating the study. The comparability phase 3 studies intended for seeking market approval should be conducted in more than 100 evaluable patients and phase 4 studies in more than 200 patients7.
Waiver of safety and efficacy study
Based on the 2012 CDSCO guidelines34, nearly 20 biosimilars, including biosimilars of infliximab, etanercept, adalimumab and rituximab, received approval/license to market in India. However, clinical studies conducted for the approval or data published were limited. The present guidelines suggest that a waiver can be provided to confirmatory efficacy and safety study if there is a high similarity with the reference biologic with respect to structural and functional characteristics, preclinical and PK/PD outcomes. The European Regulatory Authorities mandate at least one well-powered equivalence study, with the relevant patient population having at least one relevant endpoint for an appropriate duration to determine the difference in efficacy and safety between biosimilar and reference product9. In Europe, biosimilar of infliximab (Remsima) gained approval based on extensive comparability programme mainly comprising characterization, preclinical and clinical studies. Predominantly, two clinical trials (a pivotal and a PK/PD/immunogenicity trial) were conducted in accordance with international standards to compare efficacy (based on pre-specified equivalence margin), PK and safety profiles between the infliximab biosimilar (Remsima) and original product3940. The Indian Regulatory Authorities7 have made stringent regulations ensuring that there is no waiver for confirmatory phase 3 clinical studies as far as possible, especially when dealing with biologics such as monoclonal antibodies.
Immunogenicity
The immunogenicity of a biopharmaceutical agent is considered to be critical as it may affect the efficacy by cross-reacting with the active fragments, accelerating drug clearance and lowering circulating levels of the active drug and may also have the potential to compromise the safety by causing reactions such as allergy, anaphylaxis and infusion reactions41. An example is epoetin alpha, where the treatment resulted in producing a life-threatening antibody reaction (pure red cell aplasia) due to variations in the manufacturing process4243. As analytical testing or animal (preclinical) studies cannot predict the biological response in humans, clinical studies are mandatory to identify the potential risk of immunogenicity and adverse events44. The immunogenicity potential should be evaluated in comparison to the reference biologic. The present guidelines recommend providing pre-approval comparative safety data based on adequate patient exposure (sample size and duration) along with published data on the reference biologic to provide evidence that there are no unexpected safety concerns7. These considerations would be particularly important to biologics such as monoclonal antibodies and fusion proteins compared with other biologics as there is a potential for variations in manufacturing and clinical aspects.
Post-marketing requirements
According to the Indian Guidelines7, as the clinical studies performed on similar biologic before the approval are usually limited, rare adverse events are likely to occur beyond the study time period and hence may not be captured adequately. Thus, a complete pharmacovigilance plan should be put in to place by the manufacturer to further evaluate the safety. The pharmacovigilance plan should consider periodic safety update reports submission. After the market approval, safety data in addition to the previously submitted data may be required to further determine if there is any remnant risk associated with similar biologic. A pre-defined study with a single arm is required to be conducted in at least 200 patients and compared with previous data from the studies of the reference product7. The number of post-marketing studies to be conducted should be described in the pharmacovigilance plan and status of the studies has to be updated to the CDSCO. With regard to post-marketing safety and immunogenicity study, the present guidelines7 recommend (on a case-to-case basis) to perform at least one study of non-comparative design to evaluate safety and immunogenicity and to validate that the similar biologic does not pose any safety concerns and undesirable immunogenicity. A strategy for the assessment of immunogenicity with appropriate rationale has to be provided. Head-to-head comparison studies are generally recommended, and it is imperative in evaluating the safety and immunogenicity even after the product enters the market.
Extrapolation of indication
Another important consideration for similar biologics is whether the available evidence for a specific indication can be extrapolated to exhibit similarity in other indications approved for the reference biologic. Guidelines from US FDA, EMA and WHO8910 suggest providing appropriate justification based on the totality of evidence for the extrapolation of all indications. The evidence must support comparable efficacy and safety of biosimilar, individually in each of the therapeutic indications approved for reference product454647. EMA approved the first biosimilar infliximab in 2013 along with the extrapolation of all indications, including inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, psoriasis and ankylosing spondylitis, licensed for the reference biologic48. Generally, the extrapolated indications are handled on a case-to-case basis, and the final decision depends on the regulatory agencies49 (Table). In India, the extrapolation of indication is currently possible if the similarity in terms of quality or outcomes from preclinical evaluation has been established between the similar biologic and the reference product. In addition, demonstration of efficacy and safety in one indication allows extrapolation for other indications if the mechanism of action or receptors involved is the same7. The guidelines also mention that new indications that are not specified by innovator will need a separate application.
Key considerations in the current regulatory pathway for similar biologics
Interchangeability
Interchangeability status for a biosimilar is achieved if similar clinical outcomes with regard to quality, efficacy and safety in any given patient are demonstrated during switching (by the physician) or substitution (by the pharmacist) with its respective original biological product (or reference product) when compared with the reference product alone. According to the US FDA, “an interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability”50. The interchangeability status allows substitution of reference product with the interchangeable biologic by a pharmacist without the interference of the clinician who prescribed the reference biologic50. The US FDA has distinguished the biosimilars approval from the approval process for 'interchangeable biosimilar'. The approval pathway for interchangeability is stringent, and insists to establish the safety data with no additional risk to patients when switching between two biological agents compared to the use of original biologic alone5152. Unlike the US FDA, EMA does not evaluate the interchangeability of biosimilar, and the approval of the interchangeability between biosimilars and innovator products is delegated to the Member States in the European Union (EU) (Table). Each country in the EU has the authority to provide substitution bill in their respective legislative assemblies53. The approval of biosimilars does not indicate that it can be interchangeable. Moreover, it is not as simple as chemical generics, where replacement with another drug can be made without apprehension for safety issues. This has the potential for creating confusion in the interpretation of safety data collected over time as most of these therapies are for chronic conditions. The regulatory bodies in India have not provided any guidance on interchangeability. Interchangeability designation should be applied by the applicant in the dossier submitted additionally for the label, along with the clinical data to support the same. In addition to the demonstration of similarity exercise, approval for interchangeability should be rigorous and the safety data should ensure that there are no additional safety risks to the patient when switched between innovator product and biosimilar or vice versa compared to the use of the innovator product alone. Such data should always be included in the dossier submitted for the label, along with the clinical data.
Nomenclature for biosimilars
The international nomenclature [International Nonproprietary Name (INN)] by the WHO is usually followed for generic products54. As biosimilars are different from the innovator product, a distinguishable nomenclature is required to clearly identify, prescribe and dispense the correct medication. Several countries have adopted their unique naming convention55. The EU follows the same INN as the original product for biosimilars; Japan follows INN followed by letter 'BS' which stands for biosimilars and a number indicating the order that the biosimilar was approved56. In 2014, the WHO released draft guidelines for nomenclature of biosimilars called Biological Qualifier scheme, where it provided a unique four-letter identification code different from INN57. On a similar line, the US FDA has proposed to use INN, followed by a four-letter suffix that is unique and devoid of meaning58. Though the WHO has offered clarity, there is still a debate in the use and acceptance of this global nomenclature for biosimilars4858. It has also raised a question of whether following this nomenclature would bring value in traceability of biosimilars, particularly in pharmacovigilance.
Labelling
When similar biologics are licensed, healthcare professionals and patients should be made aware of the relevant data and information about similar biologic and the risk/benefit associated with it for safe and effective use. The package insert should clearly indicate whether the data were generated on similar biologic or innovator product, including differences in characterization and extent of similarity with the reference biologic on safety, immunogenicity and efficacy. Data from clinical studies must be described with statistical considerations and sample size in labelling. This is important from transparency perspective to keep the healthcare professionals, patient and other stakeholders informed about the extent of data generated on the similar biologic and its similarity to the reference product.
Conclusions
Access to quality and affordable treatment is the right of every individual. All possible efforts should be made to allow access to effective and safe medical interventions. India, like other countries having an established regulatory system, ensures patient safety with the early introduction of similar biologics, which are not proven enough for their similarity. From 2016, only a few similar biologics gained approval, reflecting the stringency in the approval process and criteria. All precautions must be taken without compromising the safety requirements and international conventions on guidelines for such products. Given the complexity of biologics, a 'one-size-fits-all' strategy for biosimilars may not be appropriate. Biosimilars of monoclonal antibodies should go through a more stringent process of approval when applied on a case-to-case basis.
Acknowledgment:
Authors acknowledge Shri Ramji Narayanan, and Dr Sangita Patil, (SIRO Clinpharm Pvt. Ltd.) for writing and editorial support, respectively.
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Financial support & sponsorship: Financial support was provided by Janssen, Johnson & Johnson Pvt. Ltd., Mumbai.
Conflicts of Interest: Drs Ramesh Jois, Sukumar Mukherjee, S. Rajeswari, and P.D. Rath have no conflict of interest to declare. Drs Vishal Goyal and Disha Gupta are employees of Johnson & Johnson Pvt. Ltd.
