Focus Group 4
Barriers to commercial manufacturing of generic LA formulations
Paul Domanico: Rapporteur
Advisors: Melissa Leavitt and Margaret Louey
Co-chairs: Lobna Gaayeb and Francois Venter
Discussed five issues that must be faced as LA molecules move from innovators or biotechnology collaborators to generic manufacturers (pre-clinical research to translation medicine to the clinic).
- Scale-up and funding – How to incentivize developers to take candidates forward?
- Technology transfer – How to ensure smooth transfer to a commercial partner?
- Innovative partnerships – Ideas for innovative partnerships for development and commercialization?
- De-risking mechanisms – How to make sure manufacturers engage in this field?
- Cost – How to justify higher potential cost to procurers?
Scale-up and funding after discovery – Cost of development and commercialization of a new drug can exceed USD 100M.
- Need alternative ways to fund the costly and high-risk next steps (safety and efficacy in humans; product development to scale a safe, effective and low-cost product; and regulatory approval).
- Examples: University of Washington (CROs); University of Liverpool (spin-out and CROs); and University of Nebraska (launched start-up to advance pre-clinical candidates to human studies).
- The real-world market for LA products is not known – innovators are interested in the LA field, but remain cautious (i.e., how many patients will be treated, how often do they need the treatment, if it is a cure what does that mean about the size of that market).
- Need to understand the value of a LA product relative to the standard of care (SOC).
- Need detailed assessment of existing SOC and how the LA product would transform care.
- Need clear success criteria at every stage (product development, commercialization, introduction, and monitoring).
Ensuring smooth technology transfer is critical to reduce timelines and cost.
- Cannot predict if the oral or LA approach will be more complicated, BUT many non-oral products involve a drug-device combination, which confer additional challenges and partnership complexities.
- Each active pharmaceutical ingredient (API) is its own special case – difficult to set standards.
- There may be value in setting platform standards (recent work by CHAI on matching API with delivery platforms to advance pediatric treatment).
- Need to be able to anticipate the complexity – the team must represent the full suite of skills required to reach the endpoint.
- Need clarity and agreement with regulatory or normative agencies on regulatory affairs strategies – begin discussions early regarding what evidence will be needed to approve generic products.
- What is necessary to generate a quality relationship?
- Successful technology transfer requires a transparent and honest relationship – regular meetings, rigorous consideration of all aspects of business and science, and joint accountability for adhering to timelines.
Innovative partnerships and de-risking strategies – the innovation in partnerships must account for the risk of introducing a new LA product that represents a new care paradigm for patients and infrastructure.
- Accessible market and impact analysis is critical to engage manufacturers, but remains hypothetical for LA products (e.g., single-administration glecapravir for HCV cure would simplify care and dramatically reduce transmission, but the overall market is not known).
- Analysis incorporates parameters associated with national guidelines, Ministry of Health (MOH) disease management strategy, existing approaches and SOC, funding envelopes, and actual and perceived value to patients and the system.
- Need to be cautious about the utility of cost-effectiveness analyses when building a business case for LA products – only one component of the decision to proceed on the national level.
- Most useful for like-to-like comparisons.
- Comparing oral and LA products is less useful – many aspects of the care cascade must evolve.
- Learning from staged rollout will be useful – iteration and trial and error.
- LA products represent a fraction of the market – not all patients will migrate to LA, and this could affect manufacturer decision-making.
- Scale.
- Generic manufacturers need product profiles (dose per unit, duration of action, size of patient population at launch, and how it will scale) to decide on the scale of manufacturing (what the cost of goods at launch is going to be and given scale and assumptions around scale what the cost or price is going to be at scale).
- LA market needs to be better understood to determine the impact on the scale of manufacturing (cost of goods at launch and scale) and what product margins are necessary to create competitive and stable markets.
- The manufacturing industry is accustomed to the oral scenario (one or several tablets per day). LA products are dosed less frequently and require fewer metric tons of active agent.
- The price of each LA administration may be higher than oral, but we do not know if the price per patient per year of LA treatment will be different – we do know that in LMICs, this cost needs to be in the ballpark of the current standard of care.
- Many patients prefer LA products, but the signal from MOHs is less clear. Community activism must remain strong. Additional operations research is probably needed to optimize care when LA products are introduced (i.e., adoption, adherence, outcomes, and systems).
- Markets may expand slowly – innovators and generic manufacturers will be cautious about how and where they enter the LA market. Need to think in terms of introduction phases, and structure business relationships accordingly.
- Next steps.
- “CAB-LA is the canary in the coal mine” – will transform our learning on how to roll out LA products.
- LA regimens will require funding well beyond what is needed to bring products to market. Sources of funding must expand to include resources from MIC governments – need to consider diagnostics, education to patients and community, etc.
Cost.
- Market for LA products for infectious diseases is too nascent to know what prices will incentivize generic manufacturers or what procurers will be willing to pay.
- MOH and finance may have different success criteria.
- The benefits of LA products might only be seen over time and when summed – the LA product and introduction may be more costly, but the overall cost of care may be lower.
- Dramatically improved adherence translates to fewer instances of disease severity (avoiding more intensive care) and fewer infections (fewer people in care).
- Simplified diagnosis, monitoring, and care cascade.
- Need transparent conversations with generic manufacturers about margins. With fewer units per treatment or one injection to cure (e.g., glecapravir), what does the margin need to be for a manufacturer to “get in the game and stay in the game?”
- Capital investment may be necessary for LA technical platforms (i.e., to manufacture novel nano materials, etc.) – need to ensure capital expenditure is separate from the cost of treatment.
- What can we learn from other verticals? We will learn a lot from the infectious disease products we have heard about today.