What happens when you need to switch your drug delivery device mid-development?

Luckily, it does not happen often. But it does happen. Your drug delivery device development is underway. You have submitted protocols to the FDA and timelines to market are set with your board and shareholders. There are contracts in place and clinical studies underway. And then you get the news…

• Your manufacturer calls and advises that your planned device platform (syringe, pen injector, auto-injector, etc.) is being discontinued or will be experiencing significant development delays.
• An early study (Clinical, Human Factors, Functional Testing) indicated that device was unsuitable for the drug or patient population.
• The Commercial team determined that a change in platform is needed for competitive reasons.

You don’t need an expert to tell you that this is a big deal, but you may need some guidance about why the situation needs critical care beyond scrambling to rush a new device into its place to keep the train moving. Right now, your team is dealing with a likely unprecedented process that will require device selection and integration with the project timeline at a hyper-speed pace. Unfortunately, in combination products, there’s no truly “off the shelf” solution that will act as a plug and play replacement. But, with budgets previously set and timeline commitments to board members and shareholders made, the pressure is on to get back on track with minimized financial or timeline ramifications. The wrong fix and approach can make a bad situation much worse, increasing the threat of patient care suffering and competitive advantage being lost due to delays in getting your product on the market.

There is no simple solution, nor a one-size-fits-all resolution. However, there is a 5-step plan that the Suttons Creek team utilizes in such circumstances.  We’re sharing that plan here to guide you in identifying your best solution faster and more efficiently.  Keep in mind that the final decision is often less about the design of the new device you will select, and more about the impacts that choosing that device relative to your original program.

Your individualized plan will depend on the multi-faceted considerations that make up your drug delivery device needs and where you are in your development process when the device change is required. Drug manufacturers can be in various stages of development, some of which will have a more difficult and costly route to a newly integrated device. Regardless of the stage you find yourself in, you will be looking for the most effective and efficient pathway to keeping timelines intact as much as possible.

To do so, you will need to find a way to free up resources to analyze your situation and potential options.  You’ll also need resources to redo vital work and/or perform bridging studies to parallel your selected new device to the costly work previously executed, to name a few ramifications. Your first step is to gather a team who has worked with a multitude of device manufacturers and has experience dealing with a midstream transition like this. If resources are lacking in that area due to experience or inability to free up the people who know best from other obligations, Suttons Creek’s pool of combination product specialists are ready to step in an lend a hand.

Step 1: Assess what you know

Assess the present program up to this point to understand where we are starting from. You will need a complete assessment of where you are in development to make decisions for each critical stage. Below is a series of questions to ask, which will paint a picture of your current situation: 

• What past analysis that led you to the original device is available for review? What, if anything, has changed?
• In what stage of development are you? Is the program pre-clinical, in-clinical, or post-clinical (commercial)?
• What is the regulatory pathway?
• What is the current program timeline? What is your goal date for submission?
• What regulatory commitments or submissions are in place?
• What data have you already collected? (This is important to use as a comparison to subsequent platform options)
• What activities are ongoing? What workflows are set up?
• What contracts are already in place?
• Where are you in your design development process? Is your design verification data generated?
• Have you done formative studies yet? Are you planning to do them?
• Have you submitted any of the protocol to the FDA yet?
• Do you have any clinical studies underway? Are any starting imminently that might be affected by your need to switch devices?
• Where are you in the process of scheduling to run parts for various purposes?

Step 2: Identify the “When”

You will need to know the “What” before you can execute the “When,” but with the train in motion, there may be immediate steps to halt work in progress, or at least to make an informed decision on whether certain work can continue during the selection process.

Now, with a thorough picture of your situation, you can now identify the ideal “when” to switch over to a new drug delivery device. If you are early on enough in your process to have not begun any studies, you are one of the lucky ones that can execute a “simpler” solution, avoiding the complexity of determining how to make the switch mid-study or between studies. For the rest of you, clinical implications for switching mid-study/clinical trial depends on the type and how similar the parameters are between the old and new device. If you fall in that likely larger category of the not as lucky, know that it is possible to change devices mid-stream, but it’s not free and it’s not necessarily easy. There are pathways and precedents that can guide you to higher probability of success.

The first question we get from drug manufacturers in this pickle is whether there is a way to salvage work already executed.  

Is your study small? 

There are examples of bridging between presentations or types of combination product, either in parallel or in the post market setting that can support the transition. Suttons Creek has seen multiple times during urgent bridging studies that small details matter, even in smaller studies. Whatever changes, however minor or cosmetic, are made from the original product to what is submitted is highly scrutinized by the FDA. This is because, with a combination product, ANY device constituent change could conceivably have an effect on clinical data, even if it seems rather small to the engineer. The FDA has seen that big effects can come from small changes, and the more changes there are, the higher the risk of big effects. Changing an entire platform, when the entire design is different, opens up a big can of risk!

The decision to attempt to bridge requires a detailed assessment, but the overarching answer is that paper-based argument can be done but adds significant risk and takes a lot of effort. Most of the time, it becomes evident that taking a small delay to rerun a study with the actual device will significantly increase your probability of regulatory approval success. Taking a smaller time/budget hit now can be a better alternative to the negative effects of an unsuccessful submission.

What if you are in the middle of a large, long-term efficacy study for a new drug?

This has a more definitive answer: It is never a good idea to switch devices mid-trial. A change in drug delivery device is an additional, uncontrolled variable you are putting in mid-way through. This type of study is highly risky to begin with, and it is critical to control everything humanly possible to prevent something from messing with the clinical data. Introducing new device in the middle of study is a fundamental change that can cause data-altering hiccups. What if, during the transition, people can’t get their doses in the middle of a study? Ten of millions of dollars-worth of study work goes out the window. However, options remain for adjusting course via parallel or subsequent bridging studies.

Can you finish out or execute a soon-scheduled study with the existing device, then change over for future studies?

For smaller studies, such as safety related studies like a relative bioavailability study or such as a Phase one PK study, yes, that is a solid possibility. When the study is not powered statistically to give a high level of detailed or comparative information and its intent is simply to provide broad stroke information, using almost any similar device in that study will suffice. If your old and intended new devices will be essentially the same should get the same outcome for these minor, less detailed studies. Your drug product formulation is the key part, and, in these cases, it can be acceptable to move ahead with the old device. However, the study type and future clinical development plan is critical, as regulators (FDA, in particular) will expect clinical data utilizing the ‘to-be-marketed’ combination product, including the device that is to be commercialized.

Step 3: Identify Selection Criteria

Just as it mattered to every stakeholder when you selected your drug delivery device/platform at the outset of your project, so does it now during this production crisis. There will be additional constraints now that the project is underway and ensuring the voice of each stakeholder is heard as you redefine your selection criteria based on your situation analysis is critical to your success. Ideal criteria will need to be weighted to establish cross-functionally agreed upon priorities.

Schedule/Timeline: You have an existing schedule and planned submission goal date, and you want to stick to it as much as possible. How rigid is it when compared to the risk of decisions made to keep the program on track? It is a good move to openly discuss acceptable wiggle room with your stakeholders and also to leave the door open for flexibility as you move through subsequent selection steps in the case that schedule constraints too severely limit quality device options.

Regulatory Elements: The answers to the following questions can help you determine the ease of transitioning to a new device.

• Has the platform been utilized for approved products? If so, what issues did those products experience during review and/or on the market in various jurisdictions? If not, have they been used in clinical studies and to what scope/extent?
• What is the device manufacturer’s overall regulatory strategy and how does that align with the drug side?
• Has the device manufacturer directly engaged with regulators and what has that experience been?
• Is a master file utilized and what information will be provided in that versus directly for incorporation into the drug submission?

Human Factors / User Needs: Be sure to apply your sometimes forgotten human factors engineering lens when compiling your selection criteria. Human Factors and User Needs criteria will center around finding something that will be operable and check off all of the necessary boxes to address the needs of your user pool. The new device won’t be exactly the same but will give the same functionality. However, the differences, no matter how seemingly small, may pose Human Factors challenges, potentially changing the use process from a task analysis standpoint or adding use complexities that can have an impact with user error and post-market competitive success.

Manufacturing / Resourcing / Capacity: A “yes” to the following questions makes the transition to a new device easier. Does the device manufacturer have sufficient development and manufacturing resources to support the given timeline? Do they have sufficient capacity for clinical scale manufacturing and/or commercial manufacturing within the given timelines? Can they provide the necessary amount of engagement and attention to the drug development team to enable success? Can the combination product be readily assembled at a variety of sites and what type of automated equipment exists to assist in that process?

Quality / Supply Chain: Ensure that the potential new device options have a supply chain and quality controls in place that can (as seamlessly as possible) integrate into your existing project structure. What level of quality is expected from the given platform – given internal manufacturing data as well as postmarket data from any approved products utilizing the platform? What does the supply chain look like, and does it contribute any substantial risk to the overall program given component supplier locations, manufacturing sites, and/or assembly processes?

Commercial / Marketing Needs: While there are a lot of options, a lot of similar products out there in categories such as auto injectors, many of the available products have been designed from a pure engineering standpoint, a functional performance standpoint, or in some cases a manufacturing standpoint. Generally, they are not designed from an aesthetic standpoint. Your Commercial stakeholders will likely have particular needs to accomplish differentiation from a competitor or create appeal for a specific target audience. They might have specific color, or other requirements, in mind. Those are things that can be customized on much longer timescales. In this case, you may be forced to go with the standard offerings which, most likely, won’t fulfill these needs. When there is no time for custom molds or colorways, can temporary fixes such as labels be utilized with a “plan B” to make lifecycle management changes after combination product approval?

Technical, CMC, Drug Product: Last, but not least, is the group most commonly driving the device selection and, of course, the critical stakeholders responsible for the success of the product. Key questions to ask are – Does the platform function with the given drug product? Are there any particular compatibility or performance issues that need to be considered in terms of design or manufacturing? Can the technical aspects of the device platform meet the program’s needs? At this stage, the existing Design History File for the current product can be utilized (Design Inputs, in particular) to determine if a given platform meets the key criteria.

Establishing a process for identifying criteria requirements, and then running through the process from a cross-functional, multidisciplinary standpoint is critical. There are few and far between keystone decisions like this, so it makes sense to go through it in a in a rigorous, thoughtful manner versus scrambling to find the first person that can tell you that they can meet your timeline. And, while this reevaluation has risen out of crisis, take advantage of this rare opportunity to make informed changes to selection criteria that otherwise would have been set in stone, had your device not fallen out from under you.

Step 4: Identify Your Options

With weighted selection criteria identified and agreed upon by all of your stakeholders, it is time to identify the options that best meet your criteria. Note the word “best” thrown in there. Odds are, your unicorn will be elusive, but hopefully, there are some good stallions to consider. While you consider your options, here’s some thoughts to keep in mind…

Timeline will feel like the most important thing.

Unlike a typical program where you’re starting off from the ground up and there is planned time built into the schedule to assess and select a device, everybody’s now under the gun, trying to make a decision now, because every minute is a minute lost and money lost. You’re already in development. You already have a timeline. You’ve told your board, your investors, your management, and now you are in a tough spot. It is understandable to make timeline the initial constraint in the new device decision-making process. You have assessed where you’re at in your schedule and, as you review your options and each new manufacturer’s timelines, you can begin to paint a picture of what that looks like going forward – how it may need to be different. When you enter in business costs, the total development cost, you will see places where you may need to pay more to save time and stay on, or close to, your goal timeline. Assessing saved time against additional costs, your stakeholder team can make informed decisions on shifting cost-saving priorities against time-saving priorities.

All stakeholders should weigh in and criteria should be weighted as a group.

Times of big and potentially costly decisions with many downstream ramifications should be made with all stakeholders’ voices heard. While engineering drives development, Human Factors and other functional aspects need to take precedence over the pure engineering needs of the device. With this in mind, make sure you are uncovering information that will lend itself to a better understanding of each device option’s functionality across disciplines:

• What human factors data exists or not out there for this platform?
• What other approved products have gone through this and what can you glean from their usability, your experience or experience on the market, etc.
• Can a proposed solution fit into your existing workflows and quality systems?
• What patient preference or other marketing information can be gleaned from studies with approved products utilizing the given platform?

While a move to “the most similar” replacement is often desired, we have found options that are a drastic improvement during reevaluation.

Mitigating risk with a highly similar new devices is definitely a strong strategy in the race to get the train back on its tracks. However, keep your eyes open for new opportunities that could shift priorities and create a bigger commercial or patient win in the end. The desire to stay on schedule is a strong influence for sure, but ‘substantial’ improvements (in terms of usability, quality, cost, etc.) should be strongly considered against potential schedule delays. It is worth noting that changing the device platform is a significant activity, and it is relatively rare to do that as a postmarket/LCM activity. If you are being forced to do it mid-development, the chance to build the ‘next generation’ of product now may be worth it.

Relationships can matter.

Is there an existing manufacturer you’ve previously contracted with – a known entity – that has viable device options? Does the “old device” manufacturer have other drug delivery device options that can swap in? Staying close to an existing partner keeps you from starting from scratch or spending too much time on contracts and onboarding.

Step 5: Define and Decide On Integrated Solution Paths

Define the end-to-end, integrated solution paths for the program based on the assessment information identified. Once those potential paths are laid out, provide a decision matrix to assess business risk, timeline, and cost across each proposed solution pathway. In some cases, there will be a clear winner, but odds are you will find multiple pathways that work, each with their own benefits and faults as you consider the against situational influences or restrictions. Your stakeholder team should once again come together in these cases to determine which benefits outweigh which faults to work toward a final decision. You may need to cycle through steps 3 through 5 a few times.

If options are minimal or dissatisfactory, it is time to assess the need for trade-off analysis, reconsidering weighted priorities, such as:

• Are you shortchanging yourself by trying too hard to stick to options based on a time requirement?
• Can you put off desired customization for a quicker fix or an intended lifecycle management activity and a post market change?
• What are the true team priorities, and can a consensus be gained with all relevant functional stakeholders in the same conversation?

Once you settle on your replacement drug delivery device there are a couple of steps not to skip before moving ahead full steam. The first is to communicate the timeline, risks, and resource needs to management and investors. You are in new territory with a brand-new game plan that carries a little (to a lot) more risk than when you first embarked on this project. Ensuring corporate alignment and enlisting executive advocates for the project’s success is imperative. Secondarily, with probable time and resource constraints, allocate additional team members needed to meet any new schedules and manage new challenges unique to this situation.   

This last piece of advice is not of a technical nature but is still very needed to keep steam in your engine after your train has derailed. Be sure to support the morale of your implementation team through this period of intense change execution. Our experience tells us that, no matter what the predicament, when your team members are appreciated with resource support, achievement acknowledgment, and practical understanding, they are a more productive unit working toward your common goal.

If you find yourself in this kind of hot spot, Suttons Creek has device manufacturer relationships in place and hands-on experience with mid-development device changes that can help guide you through it. Reach out, and our experts can help make this difficult time easier on you.

CO-AUTHORS

Jonathan Amaya-Hodges, Senior Principal Consultant, Regulatory & Quality, Suttons Creek, Inc. – Jonathan has over 16 years of multidisciplinary experience in regulated medical products (drugs, biologics, medical devices, and combination products) at multiple global companies. He has practical experience in Development/Engineering, Quality Assurance, and Regulatory Affairs for various types of combination products with a focus on drug delivery. Additional background includes digital health (including smart packaging/connected devices and software as a medical device, or SaMD) and in vitro diagnostics, along with clinical development (bridging) and lifecycle management for combination products. Jonathan engages with the global combination product community by speaking at conferences, lecturing in courses, serving key roles within prominent industry organizations, and interfacing with regulators on a variety of topics.

Steve Badelt, PhD – Steve is a seasoned expert with over 20 years of experience in combination products, engineering management, systems engineering, and business development. He founded consulting firm Suttons Creek, Inc. in 2012, which has served as the device team for pharma on over 50 combination product programs. Steve values helping others learn and grow, and when he is not consulting on behalf of Suttons Creek, he is advising startups, sitting on industry boards, speaking nationally on combination product and connectivity issues and serving as a Graduate Professor at Loyola Marymount University. LinkedIn: Steven Badelt, PhD