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Biologics and Biosimilars Regulations, Registration Process in the USA (FDA)

Updated: Aug 15, 2023

The size of the U.S. biosimilars market, estimated at USD 6.73 billion in 2021, is expected to increase by USD 9.48 billion in 2022 and USD 100.75 billion by 2029, for a CAGR of 40.2%. According to our data, the market grew by 105.4% more in 2020 than it did in 2019.

This article outlines the Biologics and Biosimilars Regulations, Registration Process in the USA (FDA).

Biologics and Biosimilars regulations  for registration in the USA

Biologics are complex therapeutic products derived from living organisms, such as proteins, nucleic acids, and cells, while biosimilars are highly similar versions of approved biologics, with no clinically meaningful differences in terms of quality, safety, and efficacy. The regulation of biologics and biosimilars is essential to ensure patient safety, foster innovation, and promote competition in the pharmaceutical industry. The Biologics and Biosimilars regulations in the USA are overseen by Food and Drug Administration (FDA) and follow a comprehensive framework.

Biologics are classified into several categories:

a. Therapeutic Biologics (Innovator Biologics): These are novel biologic products developed to treat specific diseases or medical conditions. They undergo a comprehensive regulatory review process before approval.

b. Vaccines: Biologics used for preventing infectious diseases by stimulating the immune system's response.

c. Blood and Blood Components: Products derived from human blood or plasma, such as clotting factors, antibodies, and albumin.

d. Cellular and Gene Therapies: Biologics that involve the use of cells or genes to treat or prevent diseases, such as gene therapies for genetic disorders.

e. Monoclonal Antibodies (mAbs): A specific category of therapeutic biologics that target specific molecules involved in disease pathways.

Biosimilars are classified as:

a. Biosimilars: These products are developed to be highly similar to an FDA-approved reference biologic. They undergo rigorous comparative analytical studies and may require clinical trials to establish their similarity and therapeutic equivalence.

b. Interchangeable Biosimilars: A higher standard than biosimilarity, interchangeable biosimilars are those that meet additional criteria to be substituted for the reference product without intervention by the healthcare provider. This designation allows for substitution at the pharmacy level.

Regulatory Agencies Involved:

Key regulatory agencies playing a role in overseeing the development, approval, and post-market surveillance of biologics and biosimilars in the USA:

  1. Food and Drug Administration (FDA): The FDA is the primary regulatory body responsible for ensuring the safety, effectiveness, and quality of biologics and biosimilars. The Center for Drug Evaluation and Research (CDER) within the FDA is specifically responsible for reviewing and approving biologic and biosimilar products.

  2. Biologics Price Competition and Innovation Act (BPCIA): This legislation, enacted as part of the Affordable Care Act in 2010, established an abbreviated approval pathway for biosimilars, similar to the generic drug pathway for small-molecule drugs. The BPCIA outlines the process for developing and reviewing biosimilar products and includes provisions for resolving patent disputes between innovator biologic manufacturers and biosimilar developers.

Regulatory Framework for Biologics and Biosimilars: The regulatory framework for biologics and biosimilars in the USA involves several key steps:

  1. Preclinical Development: Biologics and biosimilar developers must conduct extensive preclinical studies to demonstrate the product's safety and efficacy in animal models.

  2. Investigational New Drug (IND) Application: Before initiating clinical trials, developers submit an IND application to the FDA, outlining the proposed clinical study plan and relevant preclinical data.

  3. Clinical Trials: Clinical trials for biologics and biosimilars follow a phased approach, including Phase 1 (safety and dosing), Phase 2 (efficacy and dose optimization), and Phase 3 (large-scale efficacy and safety studies).

  4. Biologics License Application (BLA) or Biosimilar Application: To seek FDA approval, developers submit a BLA (for novel biologics) or a biosimilar application (for biosimilars), including comprehensive data on quality, safety, and efficacy.

  5. FDA Review: The FDA reviews the submitted data to assess whether the biologic or biosimilar meets the required standards for safety, quality, and efficacy.

Important documents include:

Biologics License Application

  • Chemistry, Manufacturing, and Controls (CMC) Information

  • Clinical and Pre-clinical study data

  • Comparative Analytical Studies (for Biosimilars)

  • Pharmacokinetic and Pharmacodynamic Data

  • Immunogenicity Assessment

  • Risk Management Plan

  • Labeling and Packaging Information

  • Post-Marketing Commitments

Reference Biologic Information

Comparative Data (for Biosimilars)

Patient Safety Information

Regulatory and Patent Information

Quality System Information

Biologics and Biosimilars regulations in the USA

Timelines and Fees: It takes about 2 years for the biologics and biosimilars to gain approval including clinical and preclinical trials.

Approval and Post-Market Surveillance: If the FDA approves the biologic or biosimilar, it can be marketed and distributed in the USA. Post-market surveillance ensures ongoing monitoring of the product's safety and effectiveness.

Challenges and Considerations: While the regulatory framework for biologics and biosimilars in the USA is well-established, certain challenges and considerations persist:

  1. Scientific Complexity: Biologics are inherently complex molecules, making their development and characterization challenging, and necessitating advanced analytical techniques.

  2. Data Exclusivity and Patent Disputes: Innovator biologic manufacturers often seek to protect their products through patents, leading to potential legal disputes and delays in biosimilar market entry.

  3. Interchangeability: The concept of interchangeability, where a biosimilar can be substituted for the reference biologic without the intervention of the healthcare provider, presents additional regulatory considerations.

  4. Public Perception: Educating healthcare professionals and patients about biosimilars, including their safety and efficacy, is crucial to fostering trust and adoption.

Approval of biologics and biosimilars in other countries, such as the European Union (EU) or other well-regulated markets, can provide valuable data and information that may facilitate the registration process in the United States (US). However, it's important to note that while approvals in other countries can be informative and potentially expedite certain aspects of the US registration process, they do not guarantee automatic approval by the US Food and Drug Administration (FDA). The FDA has its own rigorous standards and review processes.

Some of the key aspects that could expedite the process include:

  1. Scientific Data and Experience: Approval in other countries generates additional scientific data and real-world experience with the product. This data can contribute to the overall understanding of the product's safety, efficacy, and performance.

  2. Comparative Analytical Data: For biosimilars, analytical data comparing the biosimilar to the reference biologic from another country's approval can potentially support the demonstration of similarity in the US. However, the FDA may still require additional comparative data specific to the US context.

  3. Clinical Trial Design: If a biologic or biosimilar has undergone clinical trials in another country, the design, endpoints, and results of these trials can inform the planning and design of US-based clinical studies.

  4. Regulatory Interaction Experience: Developers who have successfully navigated regulatory processes in other countries may have gained insights and experience that could help them engage effectively with the FDA.

  5. Global Development Strategy: The success of a biologic or biosimilar in multiple markets can bolster the developer's overall global development strategy and lend credibility to their product.

  6. Regulatory Documentation: Some portions of the regulatory documentation submitted in other countries, such as non-clinical and manufacturing data, may be applicable to the US submission, potentially reducing redundancy.

  7. Bridging Studies: Developers may be able to use data generated from studies conducted in other countries as part of bridging studies to demonstrate the product's comparability or suitability for the US population.

The FDA's rigorous review process, guided by legislation such as the BPCIA, ensures that these products meet the highest standards of quality, safety, and efficacy before reaching patients. As the field of biologics and biosimilars continues to advance, ongoing collaboration between regulatory agencies, industry stakeholders, and healthcare professionals remains essential to address emerging challenges and ensure the availability of safe and effective treatment options.



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