Combination Product Industry News & Guidance

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How to build a successful combination product program

“I’m in my phase 2 clinical trial…now what?”

One of the common challenges we run into in the combination product industry is clients who don’t understand the impact of developing a combination product. Specifically, for people who are new to drug delivery devices, it’s not always clear what it takes with regard to areas such as development processes, human resources, cross-functional coordination, budgeting, and timelines (to name a few). And, for “startup” Pharma, many of the decisions you make surrounding the creation of your combination product program are driven by your short and long-term corporate goals. Are you currently looking for financing? Are you building your company for acquisition or licensing? Do you plan to develop for multiple therapeutic targets?

This article will answer many of the questions that clients who are new to combination product development tend to ask our team members on a regular basis. We will be building on the topic weekly, adding new answers to the questions commonly posed by new and evolving Pharma companies. Check back for more regularly!

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Questions about Combination Product development timelines

Questions about maneuvering regulatory bodies

Questions about human resourcing:

What is a combination product device development team?

If you’re developing a combination product, then you’ll need to integrate knowledge and expertise related to each of the constituent parts.  If you’re developing a drug/device combination product (e.g. a drug delivery system), then you’ll need the expertise of drug development team members AND device development team members. This is true even if you are not developing a bespoke drug delivery device from scratch! You’re going to need a device development team. If the appropriate quality system requirements are in place, your device development team can be comprised of employees, contractors, or outsourced teams. 

Won’t our component vendors do all this for us? Most often, no, and not completely. You may have a great supplier that can provide some development templates. They may even have human factors data a generic implementation. That doesn’t mean the work is “done.” Those are great starts, but a pharmaceutical company developing a combination product still holds management responsibility to complete the quality system requirements, establish a device quality system, develop a combination product design history file, perform post-market surveillance, and many other activities. 

You need a combination product device development team to integrate your drug with a device. A combination product device development team plays a critical role in bringing innovative medical treatments to patients. This team requires expertise and practical knowledge that go beyond drug development and even “standalone” device development. The integrated system requires more than just two separate parts. In pharma, device development team is responsible for taking a drug and increasing its value to patients by creating a solution that delivers both the effective, therapeutic benefits of a drug and the safe delivery mechanism of a medical device. This team must know device development from a quality, regulatory, engineering, manufacturing, and commercial perspectives. The team must also recognize how to integrate devices into the drug development process. The team needs to stay apprised of the the ever-changing regulatory requirements that are unique to combination products.

A combination product device development team differs from a pharmaceutical company’s drug development team.  The primary focus areas of each team are different, but must be integrated in timelines, execution, and compliance.  The drug development team concentrates on researching, formulating, and testing pharmaceutical compounds to ensure they are safe and effective for treating specific medical conditions. On the other hand, the device development team is responsible for designing and manufacturing the delivery systems, such as inhalers, auto-injectors, or implantable devices, that will deliver the drug to the patient’s body.

The collaboration between these teams is essential because the success of a combination product hinges on the seamless integration of the drug and the device. They must work closely together to ensure that the drug remains stable and effective within the device, that the device delivers the correct dosage, and that the combination product “system” meets regulatory requirements for both the drug and the device. This involves coordination to optimize schedules, integrate decisions, and address any potential issues or challenges that may arise during development.

The problems in each domain are different, and device development (even for “off-the-shelf” devices that are already commercialized) requires unique skillsets and knowledge that are not part of the drug development lexicon.

Who do I need to be successful in combination product development? What types of expertise, roles and responsibilities should my combination product team have?

A common problem in pharma is the long development and approval timelines. Regulations and practices change, and having experience on only one or two programs is often not enough to develop a fundamental understanding of product development requirements for programs that “look similar.” This can result in even longer timelines. Smart teams can all eventually figure out what needs to be done, but the full potential of a product (and ROI to a company) is in getting the project done right the first time (without a 3, 6, 12, or 18 month delay in the project schedule and/or regulatory approval cycle).

Below is a list of common roles, responsibilities, and expertise that will be needed for the successful execution of a drug delivery program from the device perspective. Note that you will usually find team members with experience assigned to more than just one drug-device program at a time.

Executive Sponsor

An executive to support the cultural, organizational, and resourcing needs of a combination product program with leadership, knowledge, and alignment.  It is critical that the executive team understands the unique needs of developing a drug-device combination.  If the executive team does not understand the impacts on the development process, it is often the case that “local optimums” are created within organizational silos and the overall organization suffers unnecessary setbacks or fails.  If the executive team is not “device experienced,” this is a major risk to the successful roll out of a product.

Project Manager

We’re all aware of the value of a good project manager. They coordinate key stakeholders, project timelines, and deliverables​. It’s critical to bring in program and project management with device expertise, even in a part-time role.  Doing so will avoid the pitfalls and mistakes that are avoided by seeing the problems coming before they arrive.

Technical Program Lead

Sometimes referred to as the “Device Lead” or “Device Responsible Person,” this is the primary technical/engineering lead and development point of contact, who is typically an experienced device engineer accustomed to necessary cGMPs like Design Controls. This person is the technical owner of all project deliverables, resources, and desired outcomes​. They provide technical oversight and functional execution through individual workstreams in support of the project. This technical expertise is applied to the technical execution of the program, as the project manager is to the project management and coordination or resourcing and timelines. To learn more about one important task that falls on your technical team’s checklist, the Design History File (DHF), click here.

Functional Team Managers

These managers oversee the individual workstream execution in support of the Technical Program Lead​.  On more complex systems, these may include mechanical, electrical, elecro-mechanical, software, and other functional area experts.

Regulatory Planning & Strategy Expert

Provides regulatory planning & strategy expertise as it pertains to the unique needs of your combination product project​.  Assists with the strategic planning of how to maneuver through the FDA’s departments and takes lead in FDA communications and meetings to provide optimal and speedy results. 

Regulatory CMC Expert

It is the specific role of the Regulatory CMC Expert to ensure a drug/biotech drug delivery system is safe, effective, and consistent in quality. Their focus is chemistry, manufacturing, and controls (CMC) aspects of drug development, throughout the product’s complete lifecycle, including postmarket.

Regulatory Device Expert

While sometimes one in the same with the Regulatory Strategy Expert, you’ll need someone, or someone(s), to execute regulatory activities related to the device portion of regulatory filings and approval of your combination product submission.

Quality Experts​ (Device Quality)

This is a critical and REQUIRED role which provides quality expertise as it pertains device development​. Specifically, the Quality Expert manages and executes the program process to ensure that your processes are in compliance with the regulations applicable to the device constituent part, and that your project is complaint to your processes. To learn about some common misconceptions about implementing a Quality Management System, click here.  

Risk Management Experts

Risk management falls within your Quality activities, and specialists are required who understand how to perform accurate risk assessments and how to recommend the appropriate actions for risk reduction to a level that suits both regulatory requirements and your business needs. For more on risk management, read “Risk Management Assessment 101 for Combination Products.”

System Engineering Experts

For larger programs, these are specialists responsible for creating the organizational systems and processes that will merge a successful device development program efficiently into your existing drug development program. They cross-functionally align all involved departments and ensure that your systems support compliance with combination product regulations (which are unique and not the sum of drug and device regulations).  For smaller projects, these responsibilities may fall on the Technical Lead.

Human Factors Lead

The Human Factors Lead is the primary manager and point of contact for all study and HF-related work​. For more information pertaining to Human Factors oversight, click here for articles.

Human Factors & IFU Experts

These specialists execute the individual workstreams in support of the Human Factors Lead​.

Labeling & Packaging Experts

These experts develop labeling and packaging strategy that satisfies drug, device, regulatory, marketing, commercialization, and business inputs. Labeling and Packaging Experts also oversee execution of labeling and packaging design and production.

Manufacturing/CMO/Supply Chain Experts

Responsible for overseeing the scale up and manufacturing of your combination product, Manufacturing, CMO, and Supply Chain Experts work closely with the Drug and Device Development teams as well as the Quality team for the sake of managing vendor relationships and quality systems. For more information on vendor quality management, read “Are You Managing Your Supplier Relationships Well Enough?”

Combination Product Postmarket Activities Expert

The Combination Product Postmarket Activities Expert is a specialist in setting up and overseeing postmarket activities needed for the combination products continued lifecycle post-launch. Responsibilities include activities such as the safety, risk management, customer feedback, training related to patient or caregiver-use of combination products, and change management. The checklist for this team member’s knowledge-base is unique from that of someone who oversees drug-only postmarket activities.

Change Manager

A Change Manager may support the project manager in managing development and sourcing and revisions.

Drug Delivery Device System Commercial/Marketing Expert:

Commercial and marketing activities for a drug delivery device system are not the same as for a drug alone. These departments become involved in device design as the voice of the customer, have a more user-based focus for marketing strategy, and have an expanded role in supporting the customer after launch. For a more in-depth look at Commerical considerations of launching a combination product, click here

[Updated 4/22/2024]

What combination product experts should I hire in-house vs capabilities that I need to (or should) outsource?

Strategic decisions around resourcing your new combination product development team can have a large impact on budgets, timelines, scalability, level of expertise, and your organizational maturity curve. Your short and long-term business goals should be taken into account, but we can go over some considerations, pros/cons, and common practices.

It is common practice for pharmaceutical companies, big and small, to outsource the following functions:

  • Device creation/supply (OEM) – Most pharmaceutical companies will buy their device, custom-made or off-the-shelf, from a trusted third party. Here’s a checklist for ensuring you are selecting the right device-constituent suppliers.
  • Testing – Tests such as CQA and EPR performance testing, biocompatibility testing, and extractable and leachables testing are not something that Pharma usually handles in-house. There may be some testing that can be done by your OEM, but most likely you will engage additional external vendors for these functions.
  • Manufacturing – It is not common practice for Pharma to set up internal manufacturing operations for drug delivery devices. This is another area that requires an outsourced partner.
  • Contract Research Organizations (CRO) – It is common for Pharmaceutical companies to outsource clinical trial-related duties to a CRO to create efficiencies and ensure better regulatory results through expert execution.
  • Other Services – Additional services that are generally outsourced to experts / not invested in as a function of Pharma companies are: sterilization, packaging and information for use (IFU) design, human factors / usability, and design verification / stability.

The scope of the team required to develop a drug delivery system is much larger than the list above, and as a startup, you have a big decision to make with regard to building a team vs. buying expertise; in other words, to hire and execute in-house vs outsourcing for each team function. Let’s start with the general positives for each option:

In-house Pros

  • Dedicated employees whose time can be allocated as your priorities require.
  • Long-term investment in people that will grow with your company and become familiar with your company culture.
  • More direct control and oversight into work, priorities, and timelines.

Outsourced Pros

  • Faster scale up without the need for recruiting, interviewing, and the potential for needing to fire and rehire when employees do not work out.
  • Easy scale down when workload reduces between projects to optimize resource allocation.
  • Practical, hands-on experience is not limited to only your company’s projects.
  • Flexibility to bring in a variety of specialists to fill a particular role vs. being limited to the expertise of one direct hire.
  • Cost efficiency of paying for services rendered and avoiding overhead costs associated with in-house staff.
  • Expertise and best-practices that can be transferred to in-house staff and implemented on future projects.

Many businesses opt for a hybrid approach, combining in-house expertise with outsourced specialists to strike a balance between control, infrastructure, cost-efficiency, and specialized skills. With that in mind, let’s take our list from above of combination product device development team roles one by one to discuss common practice and recommendations for hiring vs. outsourcing.

Executive Sponsor

This role clearly needs to be in-house, taken on by an internal executive who understands, or is trained to understand, combination product development. The Executive Sponsor is an in-house advocate for ensuring CP projects and overall program structure has the resources and corporate buy-in it needs to be successful.

Project Manager

The Project Manager for a given combination product or combination product platform program can begin as an outsourced expert to provide combination product management structure and execution knowledge to a startup. As your company grows, this position is generally transitioned into an in-house hire. They should intimately understand corporate goals and be aligned with the executive team and other in-house stakeholders and departments that will give input or provide support for their project/program.

Technical Program Lead

This role can be managed by either an in-house hire or an outsourced expert, reporting to a Project Manager who, as discussed, is generally/eventually an in-house employee. Hiring an internal lead can give you more hands-on control of the project, while outsourcing experts can result in faster start up, wider knowledge base of best practices, a more targeted specialist for the needs of that project, and an option to scale down post-project.

Functional Team Managers

More so than even the Technical Program Lead, it makes good sense to outsource functional team managers and members for the sake of targeting needed specialties, flexibility, and budgeting purposes. They are focused in on project goals and can be managed by higher-ups that connect their work to corporate goals.

Regulatory Planning & Strategy Expert

Given the often-changing regulatory landscape in the United States and globally for combination products, it is recommended that regulatory planning and strategy experts be outsourced to ensure your regulatory pathway is being directed by someone who has current experience across multiple device types and global territories. The longer a regulatory strategist is with one company, the more limited their pool of knowledge becomes.

Regulatory CMC Expert

While a startup may want to consider outsourcing a CMC Expert in order to scale up quickly and tap into a highly experienced resource immediately, this is a role that, generally, is filled in-house as a company grows.

Regulatory Device Expert

As with Functional Team Members, your Regulatory Technical Experts can be hired in-house or outsourced. In-house employees will offer a cultural continuity over time, but your pool of experts will be more limited in variety of practical experience than if you were to outsource to technical experts based on each project’s needs. As a drug company just getting into combination products, this is a good role with which to take on a less costly, non-permanent consultant vs. hiring within right away. This is particularly true when you want an FDA expert on your team…there are only so many FDA experts to go around! The best ones have insider knowledge and relationships that come from working directly for the regulatory body and have had leadership positions within the FDA and involvement in crafting the standards you now follow. If you are lucky enough to find one of these unicorns and have the ongoing work to keep them busy, do it! If not, hire one to consult as needed.

Quality Experts​ (Device Quality)

Our recommendation would be to outsource the strategic planning and “set up” of Quality Systems, allowing for specialists who have seen Quality Systems, good and bad, across the industry to assess current systems and upgrade or customize them as needed. Quality experts whose role it is to provide oversight of quality systems during device development, both internal and for external vendors and suppliers, can be outsourced or hired within, dependent on budgets and workload.

Risk Management Experts

Risk management is another area for which, depending on budgets, workload, and availability of qualified experts, it can make sense to either hire employees or outsource experts. Industry-wide best practices will come along with consultants, unless you invest not just in your employee but also in their continued education.

System Engineering Experts

Similar to Quality Experts, we would recommend outsourcing the function of strategic planning and set up of system engineering to an expert with current hands-on experience across many companies…then you could either extend their role to oversight or, with enough of a resource need, hire someone internally to mind the shop. If you choose the latter, it’s always smart to tap back into external expertise for periodic system reviews to allow for continuous improvement.

Human Factors Lead

HF is an area experiencing big innovation as corporations begin to acknowledge its benefits and necessity in the improvement of efficacy, safety, and user experience. Areas of innovation are generally best lead by experts who have wide-reaching hands-on experience, and we would recommend you start your combination product development team with an outsourced Human Factors expert as your lead.

Human Factors & IFU Experts

Human Factors and Instructions For Use (IFU) experts are called in for targeted tasks within the larger CP development timeline. Until a pharma company gets “big,” it is cost-effective to delegate those tasks to external resources and consider the ROI of scaling up to full-time employees when workload makes it a more reasonable option.

Labeling & Packaging Experts

Larger Pharma companies tend to have in-house departments dedicated to labeling and packaging. However, until a full department is needed to churn out this kind of work year-round, it is cost-effective for most other Pharma companies to hire outside experts that can apply your brand standards and marketing directives toward compliant, compelling, and user-friendly labeling and packaging.

Clinical Development Device Experts

While you could invest in a clinical device expert in-house down the road, hiring an experienced consultant to create your strategy for device integration into clinical development is a smart, cost-effective move during scale up. From there, you can continue with their outside expertise for execution and future project, or take the systems they put in place and move forward with a more permanent hire running things.

Manufacturing/CMO/Supply Chain Experts

Although you will outsource the manufacturing of your combination product, you will still need an expert on your side of the partnership to make sure manufacturing is running smoothly with your own best interest in mind. This can be an outsourced expert keeping a watchful eye and managing vendor relationships for one or more projects, or it can be an in-house hire with manufacturing and vendor management experience taking on broad oversight responsibilities.

Combination Product Postmarket Activities Expert

This role can be cost-effectively assigned to an outside consultant who works with, or helps build up, your internal post-market team to ensure that combination product systems are put in place and executed effectively after your combination product hits the market.

Change Manager

Depending on skill sets and availability/priorities, this role can be taken on by the Executive Sponsor, Project Manager, or Technical Program Lead. If you have chosen to hire those roles in-house, you may want to look into either education/training for these employees or hiring a specialist with practical experience in change management at technical/systems and cultural/organizational levels to set an appropriate strategy.

Drug Delivery Device System Commercial/Marketing Expert

If your in-house Commercial and Marketing teams have limited experience launching drug delivery devices, and especially if it is their first time to this particular rodeo, it is a wise choice to outsource strategic planning and execution oversight to an expert. These experts can also be brought in to do the necessary trainings to get your in-house team knowledgeable on their new, expanded roles and responsibilities as well as on the activities of other functional drug delivery device development teams with which they will need to provide inputs and collaborate.

[Updated 4/29/2024]

Questions about Combination Product Development Timelines

What are the key steps in the process of developing a Combination Product?

Before we put timelines in place, let’s begin with the key steps in getting your combination product developed and in the market. While it’s not quite linear, the below development pipeline depicts the steps you take in, roughly, the order in which they should be taken. (We will explain more on that as we go through each step.)

Step 1: Strategy

Most big program problems that we encounter started on the first day of the program.  It is critical to define the corporate CMC program strategy. Once you’ve decided to add a drug-delivery device, it is critical to integrate a device strategy.

Your overall product strategy must capture your business goals and consider drug development process contributions up to this point. With those inputs, the plan needs to translate those needs into the big picture steps that be taken to integrate the drug and a device(s) into one system. This will require integrating strategies for commercial, device development, manufacturing, clinical studies, quality systems, and regulatory throughout this initial process. What wasn’t planned for is often what delays programs. Most larger problems occur at the interfaces of these systems. Integration is key. CMC and device workstreams need to identify the critical junctures in the strategic plan. Early on, this needs to focus on what it will take to get to clinical, whether Ph2/3, Phase3, or a later bridge.  The plan will be periodically re-assessed throughout the program. AND…While everyone has an “ideal” plan, it is more often that the plan must be tailored to manage constraints that are internal and external to the company.

Step 2: QMS Setup

CMC process is most often defined as a quality system (QS). Device process is most often defined as a quality management system (QMS). They are analogs to each other for their respective drug and device domains.  To develop a combination product, your company must have sufficient quality processes to cover the activities of both. For more information, see this linked FDA Guidance. 

Before you move too far into development, it is essential to set up a Quality System (QS) that covers both drug and device processes. Covering quality process for both drug and device doesn’t mean you need two separate systems, and it is best that you integrate the processes to avoid problems at the interfaces between the two systems. In fact, there are optimizations that can be made to better work with your device (and other) vendors. Please keep in mind that you can implement your device quality system in a phased and “phase appropriate” manner. Doing so can limit early impact on time and resources.

Step 3: Device Selection

In drug process terms,  consideration of device feasibility and selection is ideally initiated during Phase 2 clinical trials for the drug and primary container closure and finalized by the time your drug is ready for Phase 3. Generally, it is recommended that the to-be-marketed presentation of your combination product be used in your Pivotal Study, whenever possible. However, it is possible to effectively use a device that will not be your final, to-be-marketed presentation during clinical studies. However, any potential differences (like changes in local injection adverse reaction profile, tissue plane, bioavailability of the drug and/or its metabolic profile, dose accuracy, needle depth, injection/infusion rate or user interface) will need to be addressed with the help of supplemental data, including PK bridging studies, design verification testing of the device specifications, and human factors validation studies. For more information, see the linked FDA guidance.

During this step, you are not just selecting a device…you are selecting a device partner. The device needs to be compatible with your drug, appropriate for use in the intended user population, and satisfy your commercial/marketing needs. Partnering with the right developer, supplier and/or manufacturer can help ensure you receive the appropriate level of regulatory filing and quality management support, in addition to the reliable management of postmarket phases of the combination product’s lifecycle critical to maintaining effective control of changes, complaint analysis and other postmarket activities. Click for more information on vendor selection and vendor management.

Step 4: Clinical Development

During a drug’s clinical phase, the development of a combination product necessitates a multifaceted approach to ensure safety, efficacy, and regulatory compliance. As discussed in Step 3, key device development activities you will engage in during this phase are the selection, optimization, and refinement of the device component, particularly to ensure compatible use with the drug/biologic. This involves addressing the necessary elements of device Design Control activities, including establishment of the design inputs and outputs, characterization of the combined (medicinal product + device) risk profile via a standard risk management process, verification and validation of the design specifications (including bench testing, usability validation, and potentially non-clinical/animal testing). The goal is to provide a comprehensive demonstration of safety and effectiveness of the device when used as intended with the drug product, ensuring that when used together the product performs as intended and the individual components of the combination product do not negatively impact the performance and intended use of the other constituents. The early stages of the clinical phase are also when human factors engineering (HFE) activities should be executed (although it would be even better to start discussing human factors as early as the needs analysis and planning phase). This includes market analysis and surveillance, patient focus groups, and formative studies. Such activities are valuable inputs for proactively making the necessary modifications to aspects of the product user interface or design to (1) minimize use and user errors, (2) ensure the user, device and medicinal product intended use is being met, and (3) more thorough identification of the critical use tasks. In addition to the clinical development, during this stage initial steps are taken to prepare for commercial manufacturing, including outlining the commercial manufacturing process, the manufacturing control strategy, and commercial packaging plans, all in preparation for the commercialization activities in Step 5.

Step 5: Commercial Development

During a drug’s commercial development phase for a combination product, the focus shifts from initial development to the scale-up, production, and commercialization of the combination product. This phase is dedicated to ensuring that the combination product can be manufactured reliably and consistently while meeting regulatory requirements and maintaining the safety and efficacy established in the clinical phase. Key activities include:

  1. Pptimization of the device manufacturing, fill-finish, and secondary packaging processes
  2. Scaling up production and ensuring the robustness and security of the supply chain to meet commercial demand
  3. Implementing  the manufacturing controls, change controls and  and final acceptance procedures.

This phase represents the transition from early-stage development to full-scale commercialization, with a strong emphasis on safety, quality, and market access.

Step 6: Regulatory

While Regulatory Development is placed after Commercial Development in the pipeline graphic because of the timing for marketing application filing, regulatory activities are actually happening throughout the combination product development lifecycle. Initial exploration of the device constituent is informed by the evaluation of commercial drivers and the defining of the drug and user needs. The earlier the device needs are considered in the drug development process, the more efficient the development of the combination product and the more opportunity there is to address any drug-device integration and regulatory challenges. Also, there are unique regulatory considerations for single-entity versus co-packaged versus cross-labeled combination products. On top of this, keep in mind that the European Union Medical Device Regulation does not provide a formal definition of a combination product, further complicating the regulatory landscape for combination products intended to be marketed in EU countries. Selecting the right device presentation earlier in the drug development process enables consideration of the regulatory nuances before reaching a stage of development where changes or corrections are costly in both time and money. It is important to understand the combination product regulatory and policy expectations from project beginning, as this is what will help drive the device planning and development, as well as inform what activities, data, and documentation are necessary to prepare the Design History File (DHF) – a core requirement of Design Controls as defined in U.S. 21 CFR part 820.30(j) and the backbone of your U.S. combination product regulatory filing(s).

Throughout development, your regulatory team should take advantage of opportunities for engagement with regulatory bodies like the FDA in the United States, to ensure that your regulatory strategy is aligned with requirements and expectations. And, after Commercial Development, the hard work done throughout the development process will hopefully pay off when you receive regulatory approval. To help ensure you receive approval the first time around, check out these  tips on creating a DHF that gains approval.

Step 7: Launch and Postmarket Activities

Your product has been approved by the appropriate regulatory body – congratulations! It’s time to launch. While your product was in Commercial Development, your Marketing and Postmarket Activities teams have been working. They have been developing marketing and sales materials, training sales teams, and putting robust post-market surveillance, complaint handling and change control strategies in place to monitor the combination product’s performance in real-world settings, ensuring that any potential issues are promptly identified and addressed. Launch activities also include developing ongoing user training and support programs to assist healthcare professionals and patients in using the device effectively, and setting up systems to analyze market performance and trigger needs for change management during the product’s postmarket stage.

The product lifecycle doesn’t end at regulatory approval; rather it’s iterative and the activities center around the maintenance of product reliability through consistent implementation of the control strategy, complaint handling and analysis (including fulfillment of postmarket safety reporting requirements), field surveillance and periodic trend and gap analysis. Other important activities in the postmarket is the execution of the postmarket stability commitments, pediatric research equity act (PREA), or clinical trial requirements requested and agreed upon with the regulating body.

[Updated 5/6/2024]

How does a device development timeline line up with a drug development timeline?

Explaining simply how two very complex processes work together is as difficult as it sounds. Let’s tackle this from a few different angles to ensure an in-depth understanding.

Below is a very simplified comparison of the drug development timeline and the device development timeline.

You can’t effectively begin device selection or development until you can understand the user, design and commercial inputs necessitated by the drug. So, the drug needs to get through, or close to through, Phase 2 trials, when the drug development team has sufficient data to finalize drug concentration(s) and effective treatment volume before the device considerations can be formalized. This means that device, or combination product, development occurs in much less time than the total drug clinical development timeline, starting much closer to commercial submission and launch. This does not necessarily mean that you cannot start exploring device needs at earlier stages of the overall development process, and it is actually encouraged to start thinking about potential viable presentations (e.g. syringe vs. autoinjector, administration by professionals vs. lay-users, etc.) as early as is practical to ensure early collaboration across the drug and device teams as you navigate needs considerations for the overall combination product.

The timeline comparison looks much more like the below.

The above device development phases will take approximately 4 to 6 years to accomplish, on average, compared to drug development which is typically 10 to 15 years, with clinical development averaging 8 to 10 years. The device development timeline breakdown is generally as follows:

Feasability and Design Planning: 3 to 6 months

Design Input and Design Output: 6 to 12 months

Design Verification and Validation: 1 to 2 years

Design Transfer: 1 year minimum of pre-submission activities / 1 year of regulatory submission-concurrent or post-clearance activities

Regulatory Review: 12-18 months, expecting 2 review cycles 

Note that this is an average development timeline which can vary depending on the history of development, complexity of product, and development team/company experience in this development area. There is a lot being accomplished by a cross-functional team in a (relatively) short amount of time in order to complete your combination product development on your drug development’s timeline. The graphic below is what we would typically reference as an eye-chart, or high-level snapshot of combination product development. It maps out the device development activities and example deliverables during the overall drug and combination product development phases/functions. As you can see, there is a lot involved in the overall combination product development process and it is necessary to understand these activities early to ensure any potential delays or development setback are mitigated to the extent possible.

Also important to comprehend, is that while the formalization device development activities cannot start in earnest until mid-Phase 2 at its earliest, combination product development is a non-linear process and as its name suggests, its development relies on a combination of two elements (drug/biologic and device). There are upstream and downstream implications to decisions made in early strategy sessions, which means that considerations from device activities that won’t begin until the later stages of the development lifecycle need to be proactively explored earlier in the process, before those functions are “tapped” to start their own development activities. The graphic below depicts a few of the combination product functional engagements to which we refer.

[Updated 5/13/2024]

What product choices can impact my combination product development timeline?

There are downstream effects to various choices you will make as you develop your combination product. Early decisions on the formulation, concentration, viscosity, and volume of your drug or biologic are the first development factors that will impact the design choices available to you. As for device choices, one key rule of thumb is that the complexity of the chosen device has a direct correlation to elongating or shortening effects on your development timeline. The number of activities required in your development process is defined by the complexity. Simply put, the more complex, the more activities. Higher complexity increases the number of dependencies and testing, as well as function performance testing; and, each step in preparing a device for injection is required to be tested. Also note that design changes occuring later in the process increase the number of required tests, meaning more time (and money) spent.

  

What are ideal timelines for when you should engage various CP activities within the drug development timeline?

This article would become a book if we touched on EVERY nuance of combination product engagement and when it should happen during the development timeline. Instead we will focus on general best-practices for key engagements that will better help you understand how things work. It is important to re-emphasize that the specific complexities of your combination product development program is what ultimately drives the timeline for specific development activities. More complex and novel programs (as well as programs seeking to optimize the development timeline or proactively consider bridging to more competitive device presentations) may benefit from engagement of certain activities sooner than what is typical.

Early Development

It is critical, at the earliest possible timing, to bring a diverse team in for device selection, planning, and establishing requirements and design inputs. Who should you engage? The answer is core device development functions, plus representatives from Clinical Development, Commercial/Marketing, Drug Safety, Regulatory (Clinical and CMC), Business Development and Human Factors. Without these early inputs, you run the risk of an incorrect/ineffective product being developed, mismanaging risk, timeline disruptions, and lost opportunities for design creativity.

Regulatory

We recommend starting to engage the FDA approximately 15-18 months prior to submitting a regulatory submission (IND, NDA/BLA/ANDA, etc.). You should manage at least three engagements with the agency to de-risk expensive and often time-consuming testing as well as to familiarize the FDA review division with your device. Note that each Type C meeting is scheduled within 75 days of submitting the request to review material to the FDA. The below graphic demonstrates this strategy in timeline format.

Device Integration with the Drug

When to begin engagement varies, but it’s usually during or after Phase 2. Your clinical trials will drive timelines, and CMC/device aspects of development must conform according to the progression of your clinical trials. That can put some stress on device development, so one strategy is to minimize risks in earlier phases by exploring early design needs for the product like:

  • Will the product be intended for administration by a healthcare professional or for self- and/or caregiver administration?
  • What is the planned route of administration?
  • Can we leverage prior learnings and activities from within the company combination product portfolio to support pushing device development later – even as late as during or after Phase 3 trials? (Note: this strategy can be considered risky from a regulatory expectations perspective and typically only occurs if the profile of the combination product is pretty well established or leveraged from prior development activities).

It is also an asset to really consider the development strategy within the context of the available regulatory strategies for the planned product(s).

  • Is there benefit to a phased approached to development, where the initial planned market presentation is a simpler product like a vial co-packaged with a transfer device and syringe or pre-filled syringe and later bridged to a more competitive presentation like an autoinjector?
  • What are the pros and cons of such an approach and the residual implications on the design, user and business needs.
  • Does our development situation require a later device development start that will, subsequently, require a bridging strategy? 
Device Vendor Engagement

Phase 2 clinical decision-making will impact the choice of device, so while research and preliminary conversations could happen sooner, finalization of device selection can not conceivably begin until at least mid to late-Phase 2.

CMO Engagement

At the onset of the relationship, it is wise to review your risk tolerance, business plan, commercial drivers, and quality control system/requirements with the CMO to ensure understanding and support of potential device constituent success with the drug. Other early engagements with your CMO include:

  • Coordinating on process validation work for both the drug product (e.g., fill/finish) and the combination product (e.g., assembly/labeling/packaging of the finished product)
  • Collaborating on the control strategy for the combination product
  • Planning for the scaling up the manufacturing operation, as needed
  • Aligning pharma’s human factors (design validation) strategy with CMO’s platform HF data that can be contributed
  • Creating transparency surrounding pharma and CMO’s capabilities, as well as other vendors/partners

Device quantities will be dependent on clinical study design(s). Upon finalization, it is time to engage your CMO to talk quantities and timing to determine if desired timelines are reasonable given past experiences and how it aligns with the device platform.

Prior to regulatory filing/approval, product development/lifecycle management activities focus on establishing the commercial supply chain, including logistics.

Postmarket Activities

Prior to the close of commercial development and regulatory filing/approval, your teams should also be engaging on postmarket processes, including payer reimbursement, complaints handling, adverse event reporting, and postmarket studies. These are cross-functional activities that should incorporate inputs from not just the Marketing and Postmarket teams, but also Reimbursement, Regulatory (Clinical), Medical Affairs, and Drug Safety/PV.

[Updated 5/20/2024]

Questions about maneuvering regulatory bodies

With so many departments and external vendors “touching” a drug delivery system, who is responsible for gathering the necessary elements of the regulatory submission?

As single-entity combination products are filed under a single application (determined by the primary mode of action, or PMOA), the Pharma company (market authorization holder, or MAH) ‘owns’ the regulatory responsibility for the combination product, even when a master file is used!

  • Pharma is responsible for all content in the submission, even when others (suppliers, CMOs, consultants) support.
  • Pharma is responsible for complying with cGMP (drug/biologic and applicable device quality regulation – ref: combination product cGMPs).
  • Pharma is responsible for supplier controls including documentation, inspection, testing, quality agreements, auditing, etc.
  • It is the MAH’s responsibility to create a cohesive story across all documentation within the submission, regardless of its origin/source.

That said, there are exceptions. Notably, if you have a CDRH-led combination product, the device manufacturer “owns” the development and regulatory responsibilities.

How do I know with what arm of the FDA I should be working?

As defined by 21 CFR 3.2 (m), the PMOA is the single mode of action of a combination product that provides the most important therapeutic action. It is through this definition that the lead center at the FDA is assigned, and while one might think it would be the Office of Combination Products (OCP), it is not.

One of the three below centers will be assigned based on the PMOA:

  • Center for Drug Evaluation and Research (CDER)
  • Center for Devices and Radiological Health (CDRH)
  • Center for Biologics Evaluation and Research (CBER)

For example:

Drug Eluting Stent

Primary Mode of Action: Stent opens artery

Secondary Action: Drug prevents inflammation and restenosis of artery

Regulated by; CDRH under device provisions

Drug Eluting Disk

Primary Mode of Action: Cancer chemotherapy for brain tumor

Secondary Action: Local drug delivery of drug by device

Regulated by; CDER under drug provisions

[Updated 5/28/2024]

What are the top regulatory challenges I will face with my combination product? 

1. It’s generally understood that there are inconsistencies of technical and regulatory expectations. As this industry grows, we are likely to harmonize regulations as we gain experience…replaced with new regulatory growing pains as the industry continues to innovate.

2. The timings of device development and drug development do not align perfectly, creating situations in which it is best to solidify your drug delivery device before it’s physically possible to do so. Regulatory bodies recognize the difficulties that come with this misalignment, but it is up to each sponsor to figure out the best pathway to meeting regulatory guidelines, regardless.

3. Developing “platform” device constituent parts of combination products is the most cost- and time-effective regulatory strategy. However, makers have to to consider and address the specific needs of each use case (e.g. specific drug, in specific user population, under specific set of circumstances), thus complicating this desired development pathway.

4. The best way for your particular combination product to maneuver through the submission review process of regulatory bodies, including the FDA, isn’t easily mapped out. Most companies experience uncertainty or don’t make the most effective moves as they push through the process.

5. Many companies get tripped up in updating labeling when there are cross-references between drug and device labeling.

What common mistakes can I avoid in preparing my combination product regulatory submission?

1. Not using the to-be-marketed drug delivery device in clinical studies, or implementing an inadequate bridging strategy.

2. Not considering device labeling early enough.

3. Not seeing device review during clinical studies. You should be specifically requesting that CDRH review when submitting early review submissions (IND, Pre-NDA/BLA, Type A/B/C Meeting, etc.)

4. Initiating the authoring of the hazard analysis (e.g., safety assurance case) and design verification and verification plan too late in the development program. “Early enough” would be prior to NDA/BLA/510(k) submission and/or pivotal/Phase III clinical trial. Given this timing, these items may not be a completed case or analysis, but can outline the top-level claims and general strategy for Agency feedback.

5. Not testing worst case scenarios or not challenging the specifications in expected environmental conditions

6. Not evaluating necessary device essential performance requirements on the final finished device in the stability program or not evaluating them to the proposed expiry

7. Not considering the acceptability of the device specification limits for safety and effectively achieving the intended use

Coming next, the answers to…

  1. What are the top regulatory challenges I will face with my combination product?
  2. What common mistakes can I avoid in preparing my combination product regulatory submission?

This article will be added upon over the course of the next few months, as we continue to field client questions and compile worthwhile answers that can help our readers. Please keep an eye out for updates by subscribing to our email list and following our LinkedIn page.

Coauthored by:

Steven Badelt, Phd, Founder & CEOSteve is a seasoned expert in combination products, engineering management, systems engineering, and business development. He has over 20 years of experience in the design and launch of combination products and medical devices, including auto injectors, insulin-pumps, implantable defibrillators, connectivity, and patient management software. In 2012, Steve founded consulting firm Suttons Creek, which serves as the device team for Pharma on over 120 programs. 

Courtney Evans, Principal Consultant – Courtney has over 8 years of experience in medical device and drug delivery development and regulation, including over 4 years at the FDA as a Reviewer and Team Leader of injection device combination products. They bring a passion and natural proclivity for complex combination product regulatory strategy, as evidenced by their contributions to policy development of connected “smart” drug delivery devices, on-body delivery systems, emergency-use injectors, and implantable infusion pumps.