DDReg Pharma

DDReg Pharma

Challenges in Complex Generic Drug Development

Complex drugs add more value to patients compared to simple generics as they are capable of addressing unmet needs of patients for particular conditions. However, biopharmaceutical companies encounter distinctive hurdles when it comes to the advancement of complex generic drugs. These medications, known for their intricate characteristics or the requirement of additional clinical trials, necessitate a thorough grasp of regulatory factors. This blog embarks on a captivating exploration of the regulatory landscape, unravelling the enigmatic complexities and unearthing potential solutions that pave the way for the development of these extraordinary pharmaceutical marvels. Prepare to delve into a realm where scientific ingenuity and regulatory prowess converge, unlocking the potential to transform countless lives.
Regulatory Considerations: Definitions and More
The regulatory definitions of complex generics varies between the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). According to the US FDA complex generics are generic products that have complex active ingredients, formulations, dosage forms, or routes of administrations. Or, they can be complex drug-device combination products [1]. However, EMA refers to complex generics as “hybrid medicines” that require tests conducted on the reference medicine and new data from clinical trials [2]. To gain approval, generic drugs must demonstrate both pharmaceutical equivalence and bioequivalence to the reference listed drug. However, for complex generics, additional comparative characterization and formulation studies may be required.
With the US FDA, the 505(b)(2) pathway can be more suitable for complex generics when clinical studies required for therapeutic equivalence fall outside the scope of the 505(j) pathway. This alternative route provides more flexibility in study choices and data inclusion, including the potential for additional clinical studies. A comprehensive understanding of the regulatory frameworks for 505(j) and 505(b)(2) applications is crucial for successfully navigating the approval process [3]. With EMA, complex generics follow the hybrid applications under Article 10(3) of Directive 2001/83/EC as amended [4].
Key Challenges
Some of the key challenges associated with the development of complex generics are mentioned below:
  • Developing a deep understanding of the regulatory requirements for the target market.
  • The lack of regulatory guidance introduces uncertainty, emphasizing the importance of early and consistent interactions with regulators.
  • Planning and study design for complex generics pose challenges due to the need for extensive clinical trials beyond simple generic products
  • Consideration must be given to factors such as time, location, and recruitment costs.
  • Biopharma companies should approach complex generics projects strategically, similar to innovative drug development.
  • Selecting suitable sites for complex generics projects is challenging, requiring evaluation of capabilities and commitment to compliance.
  • Rushing the development phase and working with inexperienced sites or manufacturers increase compliance risks.
  • Meticulous methods and testing are necessary for complex generics to meet efficacy and compliance goals.
  • The transition from pilot to manufacturing introduces compliance challenges, as processing issues can affect consistency and product quality.
  • Biopharma companies must carefully assess their capabilities and commitment to compliance rules, despite pressure to reduce time and costs.
  • Adherence to good manufacturing practices is crucial to avoid regulatory issues that could delay approval.
  • Neglecting proper methods and testing during development increases compliance risks.
  • Complex generics projects require rigorous testing and nuanced methods, facing additional compliance risks during the transition to manufacturing.
  • Prioritizing compliance is necessary for successful development, particularly in complex generics.
Possible Solutions
  • Biopharma companies should conduct research on similar approvals to gain insights into the regulatory landscape and necessities for complex generics.
  • Following relevant regulations is crucial in the development and approval process of complex generics, and adherence to Good Regulatory Practice (GRP) guidelines is essential.
  • Seeking feedback from regulatory authorities is valuable as it helps refine the development plan and optimize the approval process for complex generics.
  • Adopting a comprehensive and strategic approach is necessary for successful planning and study design of complex generics.
  • Biopharma companies should carefully select experienced partners to collaborate with on complex generic trials.
  • Investing in suitable trial sites and infrastructure is important to ensure the smooth execution of complex generic trials.
  • Emphasizing the value of the trial, both in terms of scientific contribution and potential benefits to patients, can facilitate recruitment and engagement.
  • Starting site outreach early in the trial planning phase helps establish strong collaborations and increases the chances of successful complex generics trials.
  • A compliance plan is crucial for complex generic projects to ensure adherence to regulatory requirements and standards.
  • Including a dedicated compliance expert in the development team can help navigate complex regulatory landscapes effectively.
  • Maintaining a balance between speed and compliance is essential to protect the brand reputation and ensure patient safety during complex generic projects.
EMA-FDA Parallel Scientific Advice for Complex Generics/Hybrid
The US FDA and EMA established a pilot program that would provide parallel scientific advice to marketing authorization applicants for complex generic/hybrid drugs. The aim of this program was to provide a mechanism for the US FDA and EMA to jointly exchange advice and views on scientific questions during the development of complex generic/hybrid drugs. These interactions would help increase dialogue between the US FDA, EMA, and the applicants, thereby providing applicants with a better understanding and foundation for making more advanced regulatory decisions, avoiding duplicate studies/unnecessary testing methods, and optimizing complex generic/hybrid product development [5].
Developing complex generic drugs requires a comprehensive understanding of regulatory considerations, careful planning, and adherence to requirements. Biopharmaceutical companies should leverage available regulatory frameworks, engage in early interactions with regulators, and approach complex generics strategically. By choosing experienced partners, investing in suitable sites, and maintaining a balance between speed and compliance, companies can navigate the challenges associated with complex generic drug development successfully. Prioritising compliance throughout the development process is crucial for ensuring regulatory approval and protecting brand reputation and patient safety.
For references and further reading:

[1] US FDA. Complex Generics News. United States Food and Drug Administration. 2023

[2]EMA. Generic and Hybrid Medicines. European Medicines Agency. 2022

[3] Klein K, Borchard G, Shah VP, Flühmann B, McNeil SE, de Vlieger JS. A pragmatic regulatory approach for complex generics through the US FDA 505 (j) or 505 (b)(2) approval pathways. Annals of the New York Academy of Sciences. 2021 Oct;1502(1):5-13.

[4] EU Directive 2001/83/EC

[5] US FDA and EMA: Pilot program- EMA FDA parallel scientific advice for hybrid/complex generic products- general principles. 2021