Category: Biosimilar Clinical Trials
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May
02

How to Plan Biosimilar Clinical Trials in India: Regulations, Process, Benefits, and Data Standards …

Efficient biosimilar clinical trials in India follow regulatory guidelines, structured processes, key benefits, and data standards for USFDA and EMA submissions.

Biosimilar clinical trials in India are witnessing growing global attention amid a significant surge in the development of biosimilars, primarily driven by patent expiries of innovator biologics and rising demand for affordable treatment options. India has emerged as a preferred destination for conducting biosimilar clinical trials, owing to its robust regulatory framework, skilled workforce, and cost-efficiency. This article explores the comprehensive approach to planning biosimilar clinical trials in India, while aligning with global standards for regulatory submissions to the USFDA and EMA.

Regulatory Landscape Governing Biosimilar Clinical Trials in India

India’s biosimilar development is governed by the Central Drugs Standard Control Organization (CDSCO) in collaboration with the Department of Biotechnology (DBT). The regulatory guidance document titled “Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorization in India” (latest revision: 2016) outlines the scientific and regulatory requirements for biosimilar development, from preclinical to post-marketing phases.

Key components of the Indian regulatory process include:

  • Comparability exercises with the reference biologic
  • Phased clinical trials: Phase I (PK/PD studies), Phase III (confirmatory efficacy and safety)
  • Pre-submission meetings with CDSCO
  • Post-approval surveillance (Phase IV studies)

Sponsors must also seek approval from Institutional Ethics Committees (IECs) and register trials on the Clinical Trials Registry – India (CTRI) before initiation.

Strategic Process of Conducting Biosimilar Clinical Trials in India

Planning and executing biosimilar clinical trials in India involves a multilayered approach that integrates scientific rigor with regulatory compliance. The general process includes:

1.Analytical Characterization: Demonstrating structural and functional similarity between the biosimilar and reference product using advanced analytical tools.

2.Non-clinical Studies: Conducting toxicity and pharmacodynamic assessments, often including in vitro and in vivo models.

3.Clinical Development:

Phase I: Pharmacokinetics (PK) and Pharmacodynamics (PD) equivalence studies in healthy volunteers or patients.

Phase III: Large-scale randomized trials to establish clinical efficacy, safety, and immunogenicity compared to the reference biologic.

 4.Data Collection and Quality Assurance: Following Good Clinical Practice (GCP) and ICH                    E6 guidelines to ensure data integrity and reliability.

  5.Dossier Preparation: Compiling data into a Common Technical Document (CTD) format for                   submission.

Benefits of Conducting Biosimilar Clinical Trials in India

India offers multiple strategic advantages for sponsors planning biosimilar development:

  • Cost-Effective Trials: Substantially lower operational costs without compromising on quality.
  • Diverse Patient Pool: Facilitates rapid recruitment and robust data generation across various indications.
  • Regulatory Alignment: Indian guidelines are harmonized with international standards, supporting global submissions.
  • Strong Infrastructure: Availability of state-of-the-art clinical research organizations (CROs), bioanalytical labs, and accredited trial sites.

Among the leading CROs in this space, ProRelix Research stands out as a trusted partner offering end-to-end support for biosimilar clinical trials in India. With a strong track record in regulatory submissions, clinical operations, and data management, ProRelix ensures that biosimilar studies adhere to CDSCO, USFDA, and EMA standards. Their expert team and commitment to quality provide biopharmaceutical companies with the confidence to conduct efficient and compliant trials across India.

Implementing Data Standards for USFDA and EMA Submissions

To ensure acceptance by global regulatory agencies such as the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA), it is imperative to align trial data with standardized formats:

  • CDISC Standards: Adoption of CDISC-compliant formats such as SDTM (Study Data Tabulation Model) and ADaM (Analysis Data Model) is mandatory for USFDA submissions.
  • eCTD Format: Both the USFDA and EMA require electronic Common Technical Document (eCTD) submissions, streamlining the review process.
  • Data Traceability and Transparency: Ensuring that raw data, metadata, and analysis files are auditable and traceable to original sources enhances regulatory confidence.

Early integration of these standards into clinical trial design significantly reduces the risk of rejections and accelerates approval timelines in the US and EU markets.

Global Biosimilars Market and Future 

The global biosimilars market is poised for exponential growth, driven by the increasing demand for cost-effective biologics, the patent expiration of blockbuster biologic drugs, and heightened healthcare accessibility across emerging economies. As biopharmaceutical innovation accelerates, India emerges as a pivotal hub for biosimilar development, offering robust clinical infrastructure, a favorable regulatory framework, and a vast, treatment-naïve patient population. This confluence of factors not only strengthens India’s strategic position in the global biosimilar value chain but also aligns seamlessly with the stringent requirements of international regulatory bodies such as the USFDA and EMA. Consequently, Indian biosimilar clinical trials are increasingly tailored to meet global data standards, positioning Indian sponsors and CROs as critical players in shaping the future of affordable biologic therapies worldwide.

Conclusion

Planning biosimilar clinical trials in India involves strategic coordination between scientific rigor, regulatory foresight, and global data compliance. India’s biosimilar regulatory pathway serves as an entry point for manufacturers seeking to utilize the considerable opportunities within the biologics market. With a favorable regulatory environment, competent infrastructure, and access to high-quality data generation, India continues to attract leading biopharma companies seeking to develop cost-effective and globally acceptable biosimilars. Organizations like ProRelix Research further empower this journey by offering expert-led, end-to-end biosimilar trial services tailored for global success.

Read More:

Understanding Biostatistical Services in Clinical Trials: A Comprehensive Breakdown

Sep
24

Understanding Biostatistical Services in Clinical Trials: A Comprehensive Breakdown

Biostatistics involves the application of statistical techniques for the design and analysis of clinical trial data. In addition to the conduct of trials which encompasses regulatory approval processes, informed consent, and patient monitoring, and safety, it is necessary to ensure that trials are appropriately designed to have suitable statistical power to meet the end point(s) and the correct trial design is employed to prove the hypothesis. As important as any of these is that the data gathered is analyzed and interpreted appropriately as it is used for clinical decision-making and that the data is collected in such a way that makes it reliable, valid, and accurate. Biostatistics involves processes such as the detection of patterns in data sets (descriptive statistics), statistical tests applied to data to make conclusions regarding populations (inferential statistics), and statistical modelling techniques to determine relationships between factors.

Biostatistical services form an important aspect of all steps in a clinical trial from design, data collection, analysis, interpretation and reporting, and post-marketing surveillance (PMS). The figure below shows the various steps in which biostatistics is used in clinical trials.

Biostatistics

Trial design and development

Before the inception of a clinical trial, it is necessary to have a robust and comprehensive statistical analysis plan (SAP) in place that provides a detailed description of the various statistical tests and analysis methods that will be used to analyze the collected qualitative and quantitative data. SAPs are required to be submitted along with the study protocol prior to initiation of a clinical trial to regulatory agencies. SAPs contain the following information:

  • primary and secondary end points
  • details for interim analysis
  • handling of missing data
  • sample size calculations
  • final analysis details
  • significance levels
  • statistical tests intended to be used
  • tables and figures to be included in the analysis reports
  • randomization plans, etc.
  • trial design (superiority, equivalence, non-inferiority, adaptive, basket, umbrella)

Data management

Biostatistics forms an integral part of the data collection process wherein it is necessary for biostatisticians to be involved in various activities related to data management such as:

  • the design of data collections instruments such as case report forms (CRFs) and electronic databases if they are used to capture patient information
  • validation of instruments such as questionnaires and patient-reported outcome (PRO) instruments
  • statistical methods to ensure the accuracy, completeness, and reliability if the data and conduct interim analysis if needed to help adjust the protocol.

Validity of data is critical for regulatory approval making it imperative to ensure the correctness of data entry taking care to avoid errors and inconsistencies. Biostatisticians must help design CRF and analyzable data sets as per Clinical Data Acquisition Standards Harmonization (CDASH) and Clinical Data Interchange Standards Consortium (CDISC) standards.

 

Statistical analysis

Often the most important role of biostatistics in clinical trials is the statistical analysis component. This involves the use of various statistical analytical techniques such as

  • inferential statistics
  • descriptive statistics
  • multivariate and linear regression models (to draw relationships between two variables in the population)
  • survival analysis (Kaplan-Meier and Cox proportional hazards model)

Data interpretation and reporting

Following analysis of datasets from sample patient groups, it is necessary for biostatisticians to be involves in the interpretation of data such that can be put into an easily readable format that can be understood and applied by clinicians and other healthcare professionals (HCPs). Cross-functional organization and communication between biostatisticians and clinical teams is necessary to help in interpretation of results and manuscript preparation activities such as the inclusion of key figures and tables to represent important findings. Submission to most regulatory agencies requires the involvement of biostatisticians to create statistical analysis reports or clinical study reports (CSR) that present the statistical data in certain formats.

Post-marketing surveillance (PMS)

Phase IV trials or PMS studies are becoming increasingly important to inform healthcare decisions from data that is gathered in the real-world. This data is often inconsistent as it is collected from disparate sources and of large volume making it essential to have a biostatistics team in place to handle this data and enable valid conclusions to be drawn from it. Biostatistics is applied in real-world evidence (RWE) analysis which involves analysis of data from real-world sources such as insurance claims, patient registries, and electronic health records (EHRs) to help identify relationships between variables. Potential safety signals can also be detected using biostatistical methods that form a part of adverse event reporting and pharmacovigilance studies. Meta-analysis, survival analysis, and risk evaluation and mitigation strategies (REMS) also involves the use of biostatistics in PMS.

Biostatistics is an integral part of all steps of clinical trials encompassing trial design to study publication. It helps ensure that the data collected is accurate and reliable and valid conclusions are drawn from the data that feed into further decision-making.

Read More:  https://prorelixresearch.com/cdisc-standards-for-biostatistics-and-clinical-data-management/

References

Mar
01

Biosimilars and Their Growing Importance in Healthcare

Biologicals products occupy a significant place in the treatment landscape of several autoimmune diseases and cancers and are most often the only choice of treatment and management of several diseases but are associated with and are limited in their usage because of their high costs and lower accessibility. Monoclonal antibodies, vaccines, and therapeutic proteins which are all biologicals are produced from living organisms by complex biotechnology processes and are more difficult to characterize than simple, small molecules resulting in high costs associated with their production and their complex and labile nature which requires highly controlled storage and transport systems. Thus, developing a so-called ‘generic’ version of biological products is important to help curtail medication costs and improve access to patients by increasing market competition and availability especially for illnesses where there are no alternative treatment options. 

Biosimilars are biological products that are highly similar to and have no clinically meaningful differences from an FDA-approved reference product. Based on inherent variation in the structure of biological molecules due to variability in sources and length, complex manufacturing process, it is normal for slight differences to exist between different batches of biological products and between the reference biological and biosimilars. Therefore, demonstrating ‘similarity’ between a reference product and biosimilar involves thorough characterization studies to compare characteristics such as purity, chemical activity, and bioactivity and human pharmacokinetic and pharmacodynamic studies to ensure that there is no clinically meaningful difference between the products. 

There are several advantages for the introduction of biosimilars in healthcare that offer an number of potential benefits to patients, payers, and providers (depicted in the figure below): 

Biosimilars and Their Growing Importance in Healthcare

 

Cost savings

Following the expiration of reference biological patents, introduction of biosimilars in the market increases competition and broadens the availability of treatment options thereby driving down the price of biologicals which further increases patient accessibility to treatments and reduces the burden on the healthcare system. Additionally, biosimilars also cost less than reference biologicals as their manufacturing costs are lower and time for development is shorter which adds to their lower price benefits.

Improved outcomes

Certain diseases can only be treated with biological products, in such instances, accessibility to biosimilars can help manage these diseases effectively as well as help in the treatment of other diseases where biologicals may be more efficacious than chemically synthesized drugs. Biosimilars also lower costs of biological treatments facilitating patient adherence to the treatments which consequently leads to better outcomes.

Increased treatment options

Biosimilars provide a broader and more affordable range of treatment options for both patients and healthcare systems allowing for improved access. In some cases, biosimilars may have a superior treatment profile than the reference biologicals in terms of formulation characteristics which is also beneficial for patients.

Healthcare system savings/sustainability

The cost savings that are realized using biosimilars can be allocated for the management of other diseases/conditions relieving the healthcare system of its financial burden by providing treatments for a wide range of diseases. 

Market competition

Improved innovation and a focus of research and development (R&D) activities by biopharmaceutical companies occur due to the introduction of biosimilars in the market fostering innovation and improvements in clinical outcomes. Market competition also forces manufacturers to decrease the cost of otherwise expensive biological products leading to a lower economic burden and increased affordability from a patient and payer perspective. 

Broader patient access

The lower cost of biosimilars increases their use by a wider population of patients of a lower socioeconomic demographic.

The above advantages of biosimilars are reasons for their increased importance and adoption in the healthcare system serving all stakeholders involved. Despite these benefits, concerns with toxicity and immunogenicity of biosimilars continue to remain important and must be carefully evaluated by healthcare providers prior to their prescription and well as regulatory authorities before their introduction into the market. Increased number of clinical trials in a larger number of patients and integration of real-world data from the use of biosimilars will help generate more data to support their applicability and increase their use.

Read More : Biosimilar clinical trials and study designs’ considerations

References

Jul
06

Biosimilar clinical trials and study designs’ considerations

Biosimilar clinical trials and study designs’ Considerations

The rising prevalence and large market share of biological products emphasize their importance as treatment options for several cancers and autoimmune diseases. In contrast to chemically synthesized molecules, biologicals are large and complex due to their natural origin with complicated synthesis and purification processes making biological products much more expensive than synthetic drugs.

To improve access to biological products at lower costs, the United States passed the Biologics Price Competition and Innovation (BPCI) Act for the development of so-called ‘generic’ versions of biologicals known as biosimilars. Owing to the structural complexity and natural origin, it is not possible to produce identical copies of biologicals unlike chemically synthesized drugs, thus biosimilars are ‘highly similar’ to innovator biologicals.

The term ‘biosimilarity’ means that the biological product is highly like the reference product notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency of the product. Thus, demonstration of biosimilarity is based on an arsenal of techniques including analytical characterization, nonclinical studies, clinical pharmacology (pharmacokinetic/pharmacodynamic) studies, and clinical studies (safety, efficacy, and immunogenicity) using a stepwise approach to biosimilar development. Although the extent and type of clinical studies for biosimilars varies depending upon the residual uncertainty following analytical and nonclinical studies, clinical trials are nonetheless essential in proving safety and efficacy.

In addition, a comparison of immunogenicity between innovator biologicals and biosimilars is critical as biologicals are proteins and can elicit different immune responses depending upon manufacturing and biotechnology processes used to produce them.

The various types of clinical studies for biosimilars are shown in Figure 1 below:

various types of clinical studies for biosimilars

 

Other clinical studies relevant to biosimilars include switching studies that evaluate the impact of transitioning patients between reference and biosimilar products and evaluate safety, efficacy, and immunogenicity. Extrapolation studies can also be done to demonstrate the use of biosimilars for other clinical indications held by the reference product and bridging studies that are done to demonstrate similarity in specific patient populations.

Study designs considerations for biosimilar Studies

Clinical trials for biosimilars are not meant to establish the clinical effectiveness of the biosimilar product. The aim is to instead to demonstrate similar clinical efficacy between the biosimilar and innovator/reference biological based on the assumption that the innovator product has demonstrated evidence of efficacy and safety in a previous development program. Keeping in mind this overarching goal, the FDA and European Medicines Agency (EMA) have released guidance documents highlighting their recommendations on the study designs that should be used to demonstrate biosimilarity as well as other factors such as sample size, duration of the study, selection of endpoints, and study population that are suitable for biosimilarity studies.

  • Parallel or crossover designs

Parallel study designs are preferred for biosimilar clinical studies as they involve the administration of the treatments (innovator biological and biosimilar) to two different groups of patients with matched demographic characteristics at the same time in a randomized manner. In contrast, crossover designs involve the administration of both treatments to the same patient at two different times with a washout period between them. Since most biologics have a long half-life, the washout period between the treatments may be extremely long and impractical. Crossover designs are not suitable when the disease is not stable as is the case with inflammatory diseases and associated with flare-ups. Parallel designs require fewer patients to achieve the same statistical power as crossover studies and are more ethical in nature furthermore, statistical analysis is also simpler when comparing two independent patient groups without confounding factors. The FDA and EMA guidelines recommend the use of parallel designs for immunogenicity assessment in treatment-naïve patients as it is the most sensitive design.

  • Equivalence or noninferiority study designs

The type of study design chosen whether equivalence, superiority, or noninferiority depends on the clinical indication, treatment effect size, availability of clinical data, and regulatory requirements. Since biosimilarity studies are intended to demonstrate the similarity between the reference biological and biosimilar, equivalence designs are preferred by most regulatory bodies.

The null hypothesis for equivalence trials is that the biosimilar is either superior to or inferior to the reference product based on a prespecified equivalence margin. The equivalence margin is defined based on historically and scientifically justified differences in treatment effects. Although symmetric superiority and inferiority margins are most used, asymmetric margins may be used in cases on non-dose related toxicities as they require smaller sample sizes. The most difficult aspect of equivalence study designs is defining the equivalence margin as it should be accepted by regulators, depends on the therapeutic indication and the efficacy endpoint, and determines the sample size. However, regulatory bodies do not specify equivalence margins such that this aspect needs careful consideration.

In addition to equivalence studies, the FDA and EMA also accept the use of non-inferiority study designs provided that their use is appropriately justified. Non-inferiority studies require a smaller sample size than equivalence designs and their use is justified in cases where the reference biological is used close to its maximal level of clinical effect.

The null hypothesis in these studies is that the biosimilar product is inferior to the reference drug based on a pre-specified equivalence margin. However, the conclusions from noninferiority studies should be interpreted with caution as it cannot exclude the increased activity of the biosimilar which may be associated with greater adverse events. Therefore, in most cases, equivalence designs are more rigorous and should be used as a default for biosimilars unless appropriate justification is provided to use an alternate study design.

Although regulatory authorities provide guidance on endpoints, sample sizes, and study designs, they do not provide specific equivalence/noninferiority margins that should be used or even interpretation of results from equivalence and non-inferiority studies.

Thus, it is extremely important for sponsors/investigators to discuss all aspects of biosimilar study designs with regulatory authorities to allow for the approval of biosimilars which will increase access to biologics at a lower cost. Sponsors should use scientific justification from historical data to support all aspects of study design and if necessary, discuss their proposed plan with regulators to ensure smooth progress of their clinical trial.

Read More:

Changes to CDSCO’s Rules for Clinical Trials in India: New Drugs & Clinical Trial Rules 2019

 References

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