Similar biologics in India: A story of access or potential for compromise?

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.

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.