4 Ways To Avoid Failure In Phase III Clinical Manufacturing
By Sylvia Tsengouras, Senior Clinical Supply Chain Manager, Fisher Clinical Services - Part of Thermo Fisher Scientific; Isabelle Lafosse, Head of Technology Transfer, Patheon; Kara Faford, VP of Commercial Finance, Patheon
More than half of the novel drugs developed in the United States and approved by the FDA have come from companies with fewer than 500 employees, making small to midsize companies the drivers of innovation in drug discovery and development.1 Yet, as with any venture, a promising molecule can only get you so far. Proper planning is vital, especially for biopharma companies facing far greater resource and financial challenges than their manufacturing counterparts in large pharma.
So, while you may be dreaming big, your budget could be limiting the control you have over your long-term plan and may lead to decisions based primarily on pricing. A lack of resources can also impede your road to success, as it takes a village to bring a drug to market. For some, the answer may be to work with a CDMO with the established processes and depth of expertise needed to mitigate the risks of drug development. However, any emerging company entering the biopharma space must understand the challenges they will face and how to prepare for them in order to plan appropriately. What you do today dictates the options you have later when the costs — and the stakes — get even higher.
1. Consider Your Exit Strategy Early
The goal for most emerging companies is to get a drug through the early phases of development and sell after proof-of-concept (POC). Therefore, the strength of your balance sheet and how you would be valued by prospective buyers should always remain a consideration throughout development. It is important to make decisions that keep your company appealing to potential buyers. For example, while you may consider investing in your own assets as a strong strategic play to retain control over the process, you may end up losing your appeal with investors by carrying too much capital. This means potential buyers have less money to invest in more R&D or other parts of the process, such as commercialization and marketing. If they do not feel they will have enough funds left to invest in their future and put more molecules in their pipeline, your company becomes much less attractive.
A strategy to reduce capital on your balance sheet is leveraging the facilities and expertise of a strategic partner, so you must select one that has the necessary capabilities to scale with the molecule. If you do not, and you decide to see it to market, you will need to repeat the timely process of sending out requests for proposals (RFPs), vetting vendors, and negotiating contracts and pricing if and when that molecule moves to future phases. In many cases, picking a CDMO with end-to-end development-commercialization solutions will save you money and time, as the hours and costs that go into understanding your molecule only need to happen once. If you continue to switch partners, the cost of that service work will be factored in every time a development team must get up to speed on your molecule. This is the case even if you are confident you will eventually sell. Investors appreciate your due diligence in selecting a strategic and reputable partner, so they can trust the validity of testing and credibility of the CDMO’s work up to that point.
2. Effectively And Efficiently Manage Your Clinical Supply
Phase I studies usually have only a finite set of subjects, so it is easier to ensure there are enough drugs to cover the doses you need. As you move into the later phases, your patient pool gets bigger, so it becomes crucial that you manage your clinical trials properly to avoid running out of supply. This can happen for a number of reasons, such as:
- Underestimating actual supply quantities – Knowing how many patients a trial will have in it is a key factor, but the rate at which they enroll is also key. If you do not stagger supply appropriately, you may run out or waste too much supply before the trial is complete. It is also important to make sure supplies are available at every site, regardless of whether a subject is enrolled there. Without enough supply ahead of time, any subjects that get enrolled later may be asked to come back, which is not always possible and can complicate the process if timely lab work was completed prior to their arrival.
- Not projecting correct depot quantities – If your clinical trial is global, you must account for intermediate depots, or sub depots. For example, if supplies are being packaged in England but are being sent to Israel, you must compensate for the fact that Israel requires an in-country depot. Now you must diversify your inventory quantity and send more supply to Israel because you need to be able to have it there in the event that those subjects and sites start to produce more patients than expected. In addition, you must consider other factors that could impact delivery to a depot, such as import licenses and procedures, transit time, and customs clearances.
- Not accounting for temperature sensitivity and/or expiration of biologics – You may lose supply to temperature excursions or even end up with wasted supply that has passed its expiration date if you do not prepare for the sensitivity of biologic drugs. In some cases, a country may not even let you import product if it has an expiration date within six months of delivery.
While clinical trials are intended to test the efficacy and safety of a new drug, they are still supplying medication to patients in need. The last thing you want to happen is something that prevents you from being able to deliver those drugs. Therefore, as the complexity of today’s drugs and their supply chains increase, having the knowledge and experience of managing clinical supply becomes invaluable. If you possess this expertise internally, then you have the tools necessary to take your drug through the development pipeline. However, if you do not, vet prospective CDMOs on their clinical supply management experience when selecting a partner in early phases. An experienced clinical supply professional is:
- knowledgeable in forecasting and simulations.
- a veteran at inventory management.
- well versed in a multitude of interactive response technology (IRT) systems and can support IRT setup and management.
- skilled at risk analysis and mitigation.
- possesses the necessary resources to manage the design, setup, packaging, and preparation to make sure your supplies are appropriately viable for every country in which you intend to conduct studies.
There are always elements of uncertainty that come about as unforeseen problems arise. Working with a partner who knows how to manage an inventory crisis effectively and can come up with options to resolve it may mean the difference between keeping the trial going or experiencing enrollment postponement, missed dosings, dropped patients, and other delays that have an adverse impact on the progress of the trial.
3. Protect And Preserve Your Product Knowledge During Tech Transfers
Technology transfers are a vital element of moving from the development stage to commercialization. Seamlessly passing on the collective knowledge about your API through multiple sets of hands is an integral part of bringing your drug to market, not only effectively but also quickly. With competition increasing substantially, being first to market can sometimes mean the difference between success and failure. So how do you make sure you are transferring your process adequately to the next phase of the lifecycle, so that it can be produced in a reliable and economic way?
Tech transfer planning is a relentless practice of identifying potential issues and proactively working through them, so you can maximize the chances of success for the project. First, begin planning how you will complete your tech transfers by making sure you understand the market you are entering. Not just the indications but also the likelihood of entry into it and what competition exists, so you can think about scale and potential sourcing strategies. Having those conversations in Phase III or even earlier allows you to start thinking about commercialization and supply and helps your team identify opportunities for improvement. Whatever plan you come up with to carry the project through to completion serves as the backbone for project execution and monitoring.
Anticipating risks and planning against may seem like an unaffordable investment in time and resources. However, it drives preparedness and enables the team to overcome any challenge they face. As you develop your tech transfer plan, consider what else you can do to mitigate risks. For example:
- Evaluate key areas, such as materials, manufacturing, safety, analytical methods, personnel training, volume forecast shifts, etc., to determine where problems could potentially occur.
- Review your key connection points to make sure that each activity feeds into the next and that any assumptions are realistic.
- Develop mitigation plans to proactively address potential risks.
The ability to complete your plan right the first time is what is going to drive how fast you can go. Communication is the foundation of this. You must make sure all teams are connected and multifunctional. The more you enable the subject matter experts to reach out and have direct conversations with each other, the smoother, faster, and more optimized your process will be. By having a structured process for project management and communication, it allows everybody on the team to understand the project and for the project manager to adjust the plan as needed. Every project requires a certain level of attention and dedication in order to be successful, so adapting to changes along the way may require bringing in additional resources if needed or elevating the conversation to higher levels within the team.
If these resources are not in-house, be sure your outsourcing partner can cover the gap. They can provide structure that includes a project manager who brings continuity to the relationship as well as a multifunctional team that will look into all of the different aspects of the project, from supply to method to quality to technology. If you start with a vendor who has the capability to do the development all the way through commercialization, it presents a significant advantage by minimizing handoffs and minimizing costs. Having a long-term view of your project allows you to make more educated decisions earlier, which can increase speed to market. In addition, the body of knowledge about your product stays with the same team, even if the SMEs change along the way. This facilitates future tech transfers, ultimately saving you time and money.
4. Procure Enough Manufacturing Capacity
As your molecule passes POC and your clinical trials expand, you need to make a decision about whether you want to commercialize your drug. If your strategy has always been to sell and you have continued to make decisions that keep your drug an attractive option for potential buyers, then you are ready to take the next steps in selling it. Yet, if you decide to take your drug the rest of the way to market, or even if you are still unsure of what to do, the next hurdle will be manufacturing capacity.
The financial investment and time needed to prepare are much less than for a new build if you already own the capacity necessary to bring your drug to market. If you determine you do not have the capacity necessary, then you must begin the arduous process of planning new capacity. Engineering studies and plans must be completed, facilities must be built or modified, and equipment must be ordered, installed, and qualified. This all can take anywhere from three to five years to complete, which means that any capacity decisions you make will be made years before you know the fate of your drug. And with a price tag of a new facility resting between $400 million and $500 million, the accuracy of demand forecasting becomes critical. Unfortunately, the industry has always grappled with the complex issue of demand forecasting. Underestimating demand can result in a loss of sales, product risk, and overworked employees, while overestimating can result in a misappropriation of capital. Thus, you may not be willing to take the risk, or procuring capacity may just not be possible based on budget restrictions.
The other option is to outsource capacity, where selection of a competent, flexible CDMO is essential. When you outsource to a partner with the experience and means to take you through scale-up from Phase III to commercial production, you add resources to your team that can assist with supply planning, logistics, and operations. This advantage also gives you access to the newest equipment and technologies, such as continuous manufacturing and patented technologies. If you hit a scale-up road block, a qualified partner brings the scientific expertise needed to jump in and quickly identify a solution. Finally, outsourcing manufacturing for Phase III establishes a secure supply chain ahead of NDA approval, lessens risk incurred by capital investment, and provides flexibility in supply.
In the end, regardless of whether you do these things on your own or with a partner, making sensible business decisions requires careful consideration of many details throughout development and manufacturing. Having the tools, resources, and knowledge to know what to do and when can make or break the future of your company. Therefore, seek to understand what you do not know, so you can forge a pathway to the most efficient road to success.
- APhA, FDA: Helping small businesses get big results — https://www.pharmacist.com/article/fda-helping-small-businesses-get-big-results