Pioneering access to complex generic products 

Claire D’Abreu-Hayling, Chief Scientific Officer at Sandoz, examines how generic products can relieve industry pressure and improve access to essential medicines.  

Off-patent medicines today account for about 80% of global prescriptions at an estimated 20% of the total cost. This will continue to be the case going forward, but the nature of the off-patent landscape will evolve in line with ongoing changes in the segment’s ‘pipeline’: the originator products of today, which will become the generic and biosimilar medicines of tomorrow.  

Originator pharma companies are developing ever more complex products, which are transforming the medical landscape, but their cost places an increasing burden on healthcare budgets worldwide. For instance, the complex injectables segment alone could account for a quarter of the total number of upcoming loss of exclusivity (LOE) opportunities. So, there is a huge potential for generics companies to take the lead in relieving this burden and driving sustainable access to advanced therapies, particularly for currently underserved patient populations. 

In September 2021, the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) announced the initiation of a pilot programme1 to provide parallel scientific advice to pharma companies applying for marketing authorisation for generic versions of hybrid products and complex generic drug products. However, despite such positive efforts to support the advancement and faster approval of complex generics, a lot still needs to be done to enhance access to these important medicines.  

Many medical products that went off-patent years back still do not have a generic equivalent, primarily due to complexity or uncertainty concerning requirements to obtain approval. If we take the case of complex injectables, for instance, there are several long-acting injectables in the market with little or no competition.  

The reasons are many. For instance, there are several liposome, microsphere, suspension and nanoparticle injections with no generic versions, primarily due to the complexity surrounding the active pharmaceutical ingredient, functional excipients or formulation, as well as significant investment requirements and a relatively high risk of failure. In the meantime, the absence of generics is costing payors and patients billions of dollars in unnecessary additional healthcare expenditure. 

What are complex generics? 

Complex generics comprise a diverse range of products. This includes products with complex active ingredients or complex formulations, drug-device combination products, or complex routes of delivery. It could also include specialty products that are harder to develop compared to standard generic products. Examples include synthetic peptides, oligonucleotides, liposomes, complex injectables, ophthalmic suspensions, and nasal sprays. In many cases, it is also challenging to apply traditional bioequivalence methods or to ensure clarity about the comparison model (in-vitro/in-vivo) needed to gain health authority approval. In addition, some complex generic products require substantial investments into R&D, scale-up and commercial manufacturing equipment and footprint, as well as needing the set-up of complex commercial channels. All of this results in less competition for these products. 

It is little wonder then that the diverse nature of these products raises several challenges for regulatory agencies when it comes to providing clear guidance to companies interested in developing generic alternatives to these complex products.  

Developing complex generic products requires a deeper understanding of the characteristics of the reference medicine compared to when this was developed by the product originator. For instance, the development team would have to perform a deep characterisation study to understand the goalpost and which formulation might be successful or which characteristics might influence the pharmacokinetic (PK) study while determining how the body handles the substance. In addition, it requires the generic manufacturer to invest in:  

  • A more advanced level of scientific expertise than is required for standard generic development 
  • More planning and a more intensive development process (characterisation / comparability) 
  • Deep understanding of the regulatory, quality, pricing/reimbursement environment 
  • Significant upfront investments as well as high development cost 
  • Early scientific engagement with the Health Authorities to manage the complexity and uncertainty around the approval pathway and identify possible alternative approaches 

There are several opportunities here for regulatory bodies to rethink existing guidelines for developing and manufacturing such products and to provide new guidelines that will help pave a clearer path for complex generic products. Also, as an industry, we can get more involved and potentially steer the conversation to better inform health authorities’ thinking about product development and innovation for complex products. Let us take a look at some of the challenges and opportunities involved in pioneering access to complex generic products. 

Opportunities  

Originator pharma companies are developing more and more complex products these days. These advanced therapies are transforming the medical landscape and are emerging as the future of patient care. However, the cost of these therapies makes this out of reach for a large part of the patient population across the globe and places a huge burden on the healthcare system even in advanced markets. There is significant need for more cost-effective generic versions. This opens a huge opportunity for generic pharma companies to explore developing complex generic drugs. 

Even a cursory survey of the originator product landscape indicates that over the course of the next few years, we are likely to see patents expire for several important medicinal products. The complex injectables segment alone could account for a quarter of the total number of the loss of exclusivity opportunities. The injectables space includes multiple complex types of products including long-acting release (suspensions and microspheres), liposomal products, suspensions, iron colloids, polypeptides and oligonucleotides. To put this into perspective for oligonucleotides, approximately 15 products2 have been approved between 1998-2021 and, approximately, an additional 80 compounds are currently in Phase II/III clinical trials. In all, around 130 clinical trials are ongoing for oligonucleotides. When it comes to peptides, more than 80 were approved in the US alone, with 8% of FDA branded drug approvals being for peptides during 2016-2021. 

Potential savings for the healthcare sector? 

According to a 2021 report by Association for Accessible Medicines, complex generics could save the US healthcare system approximately $1.3 billion per year3. In the European Union (EU), where spending on healthcare has been on the rise due to an ageing population, lowering costs is important to the long-term sustainability of the healthcare system. Generics have already contributed to significant savings for patients. According to IQVIA, off-patent medicines accounted for over 90% of all prescription volume (in standard units) but less than 50% of the value in the EU. Encouraging the development of complex generics can significantly contribute to strengthening the healthcare system and meeting unmet medical needs by enabling access for underserved patient populations.  

Challenges 

Developing and commercialising complex generic products pose significant challenges including: 

  1. Patent challenges – Strategic patenting employed by originators are an important part of protecting intellectual property, but in some cases can delay or even block generic competition and prevent patients from accessing more cost-effective alternatives. In the case of complex generics, we often see a significant delay as a result of numerous secondary patents filed by originators. This is especially the case when it comes to blockbuster drugs where the unmet patient need could be significantly higher.  
  2. High development and scale-up costs – Developing generic versions of complex products require significantly higher levels of scientific expertise and may involve a more complicated and challenging development and manufacturing process as compared to standard Gx products. Also, sometimes traditional bioequivalence approaches will not be possible and investment in expensive clinical trials are warranted. This can include hard to recruit patient populations with rare diseases adding to long development timelines. 
  3. Limited expertise in new high barrier testing methods and technology – For example, determining the type and amount of polymer (excipient in the drug product) and the optimal processing conditions to ensure the excipient is at the right level in the drug product and ensuring the release profile is consistent with that of the RLD (reference listed drug). Characterisation technologies are key to the determination and ultimately the performance of a polymer in the drug product and can be challenging, to say the least. Staying abreast of new techniques/methods is also important due to scientific advances.  
  4. Long approval timelines – On an average, most applications for complex Gx products take at least three review cycles before they are approved. This adds between 1.5 to 2.5 years to the development timeline for a typical complex drug product, thereby increasing costs and delaying the overall process.  

Additionally, enabling access for complex Gx as compared to standard Gx products requires an active approach and considerable investment to ensure market uptake. These factors alone pose a significant threat to a Gx company’s ability to successfully develop, scale up and launch a complex product. Other significant challenges include: 

1. Regulatory & Policy: As mentioned earlier, regulatory uncertainty for generic drug developers rises from various factors including the lack of standard regulatory guidelines for complex Gx. In the large part, this is also due to significant diversity in the types of products that together comprise Complex Gx, which is compounded by the limited experience both Gx companies as well as health authority Gx reviewers have in this space. 

  • Lack of harmonisation among the various regulatory agencies, as there are significant differences in the submission criteria between the different global regulatory authorities (US FDA, EMA in the EU, ACSS, among others) 
  • Product complexity, in itself, poses several challenges in defining clear pathways  
  • Lack of access as well as higher spend for the RLD product 
  • Environmental legislation, e.g., reusable plastics, lower global warming potential (GWP) propellants etc.  

2. Scientific and Ecosystem Challenges: In addition to the significant investments required in development, manufacturing, and clinical trials, and the availability of skilled talent across areas such as device, formulation, analytical, regulatory, clinical, and immunogenicity, Gx companies have to deal with several other technical challenges including: 

  • Comparability and characterisation – Lack of common PSGs (Product Specific Guidance) 
  • Access to laboratory capabilities and expertise in methodologies used. Also, the limitation of using labs for only certain kinds of products and not others as well as equipment limitations 
  • Challenges connected to conducting clinical trials / bioequivalence (BE) studies 
  • Higher requirements for clinical endpoint (PD) studies 
  • Contract research organisation (CRO) – long timelines to deliver due to limited CROs with expertise and/or lead times 
  • Device patents often expire later than drug substance patents  
  • Challenging analytics and in vitro-in vivo correlation (IVIVC)  

Specific product class challenges also exist across peptides/oligonucleotides, drug-device combination products, liposomal products, nasal sprays, and respiratory products. If you take the case of combination drug device products, the FDA’s current thinking4 on the comparative use human factor studies (CUHFS) or how to properly calculate non-inferiority margins to employ a CUHFS is still at the draft stage. Further clarity into acceptable study designs and noninferiority margins that can be employed in CUHFS via regulatory sponsored workshops, trainings and focus groups would be beneficial. 

Initiatives already being taken by regulatory agencies to enable access 

The US FDA has been actively working on various initiatives to help pharmaceutical companies develop generics for complex injectables. Some of these initiatives are: 

1) CGT (Competitive Generic Therapies) Act, a new pathway for Gx companies to request a CGT designation for a drug with “inadequate generic competition” that provides guidance to expedite the development and abbreviated new drug application (ANDA) review process 

2) The Center For Research on Complex Generics (CRCG), which aims to enhance research collaborations with the generic industry, advance dialogue, increase understanding of complex products and practices, while exploring new ways to increase access to safe and effective generic medicines 

Generic Drug User Fee Amendments (GDUFA III) program providing Product Specific Guidance (PSG) for generics wherein the FDA has committed to issue PSGs for 50% of new complex products within two years after approval and for 75% of such products within three years after approval beginning in FY 2023  

The US FDA has also been conducting regular workshops to clarify its expectations and practices for conducting formulation assessments with generic products under development across different routes of administration, and to discuss best practices and lessons learned with the goal of minimising the potential for formulation-related issues that can otherwise adversely impact a regulatory decision on the filing or approval of an ANDA. 

In addition to harmonised and standardised regulatory approaches for complex generics as well as consistency with requirements for approval across submissions and geographic locals, innovative approaches and tools leveraging big data, advanced statistics and machine learning could further contribute to optimised programme design and reduced bio-study burden. We are witnessing an increasing openness from regulatory authorities for modeling-supported approaches in standard generics, particularly in in-vitro and in-vivo correlations, bioequivalence and clinical studies, and risk-based predictive stability, to name a few. In the future, we expect a wider adoption of similar approaches, as well as device-specific in silico models and simulations, also in complex generics to establish the framework for including insights from such data-driven technologies into regulatory submissions. 

In conclusion 

Complex generics can provide significant cost savings to the healthcare system and improve patient access. Although some complex generics have come to market in the last few years, a significant number of important complex products are off patent but still lack generic competition. With more complex products on the verge of losing exclusivity and patent protection, it is important to achieve demonstrable progress in increasing access to complex generics. This can primarily be achieved by introducing policies to accelerate the approval of these products. The efforts by EMA and FDA to harmonise will hopefully help reduce the costs of development, and unnecessary duplication of clinical trials for both geographies and lead to improved access to high-quality products in a timely and predictable manner.  

To enable this and also tap into the huge opportunities this offers, the pharma industry needs to commit to making the high investments required, including investments in platform technologies, to build and retain core knowledge. This would require further assurances from policy makers in addition to bringing the industry together where possible to work together in tackling emerging challenges quickly and effectively and advancing the cause of patients.  

Regulatory agencies and other stakeholders have made efforts to facilitate a more robust complex generic marketplace, but these have thus far resulted in process improvements more than outcome gains. Therefore, encouraging robust and timely market competition for Gx products will help bring greater efficiency and transparency and further enable a more robust ecosystem for advancing complex generic product development. 

References: 

1: https://www.ema.europa.eu/en/documents/regulatory-procedural-guideline/pilot-programme-european-medicines-agency-food-drug-administration-parallel-scientific-advice-hybrid/complex-generic-products-general-principles_en.pdf 

2:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8876811/  

3: https://accessiblemeds.org/resources/press-releases/complex-generics-could-save-us-health-care-system-approximately-13-billion  

4. https://www.fda.gov/files/drugs/published/Comparative-Analyses-and-Related-Comparative-Use-Human-Factors-Studies-for-a-Drug-Device-Combination-Product-Submitted-in-an-ANDA–Draft-Guidance-for-Industry.pdf

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