Combination Product Industry News & Guidance

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 human resourcing

Questions about Combination Product development timelines

Questions about maneuvering regulatory bodies

Questions about Risk Management

Questions about evaluating delivery devices for your drug/biologic program

Questions about aligning stakeholders

Questions about working with your OEM

Guidance for Combination Product executives and leadership

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. (Click here for an insightful article about creating a combination product “ecosystem” within your Pharma culture.)

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.

[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]

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. Optimization 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]

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.

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

[Updated 6/4/2024]

If I am looking at a more global combination product program, how are things different between the United States regulation and other territories? What should I be aware of as I enter various territories?

Global regulation harmonizing bodies like the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and International Medical Device Regulators Forum (IMDRF) consider synchronization efforts for combination products, despite not explicitly covering them. Many ICH guidelines apply to CPs, including ICH Q12 which includes CPs in its scope. While they continue their work, it is necessary to look at each country/region for its unique systems and rules.

United States

The FDA (Food and Drug Administration) is the single regulatory authority responsible for reviewing medical devices, pharmaceutical drugs/biologics and combination products, though different parts of the organization (centers) are involved in certain reviews. Policy development for and coordination of combination products is overseen by the Office of Combination Product (OCP). Which center is assigned review responsibility is determined by the type of application, and inter-center consults will occur by that center’s facilitation. For combination products in particular, the lead center is determined by the primary mode of action (PMOA).

There has been established policy and guidance on cGMP, medical device Quality Systems and combination product reviews in the United States for over 20 years. This provides a developed system with clear avenues for engagement (Q-sub, Type A/B/C meetings, etc.). However, engaging with the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) can prove difficult if you are a device manufacturer without a pharmaceutical partner. That is why it is generally recommended that you first establish

To support combination product submissions, Master File options are readily available and often used for the device constituent (MAF) and for container closure components and, potentially, device constituent parts that are considered secondary container closure (DMF).

European Union

There is no coordinating body for combination products in the EU. Further, there is no formal (regulated) definition of combination products. Multiple regulatory authorities manage submission review and approval under the union’s Medical Device Regulation (MDR) rules, including the EMA (European Medicines Agency) and/or drug Competent Authorities (CA), Notified Bodies (NB), and device Competent Authorities. The EU has a new and evolving process, given Notified Body involvement in unfamiliar products and division between “drug” and “device” parts, which includes a multi-step review requiring NBOp (Notified Body Opinion) prior to submitting a drug for Marketing Authorization Application (MAA) or appropriate variation.

There are fewer and more constrained routes for regulatory engagement in the EU, as Notified Bodies are legally restricted from providing consultation. EMA and/or drug CAs can provide advice but may not be knowledgeable in the device part.

Unlike in the United States, no master files are available for use.

Canada

Canadian oversight is relatively similar to the United States. This nation is currently reassessing their combination product regulations.

United Kingdom

The UK is currently following the OLD European Unition approach (MDD) until laws are changed following Brexit. There is no formal device assessment, but the MHRA (Medicines and Healthcare products Regulatory Agency) has the competence to look for device data.

Switzerland

The Swiss have incorporated the EU’s Medical Device Regulation (MDR) into law and thus Article 117 (categorization of a product as a medicinal product or a medical device based on its mode of action) also applies there. However, different Notified Bodies are recognized due to a lack of an active Mutual Recognition Agreement (MRA) with the EUand Swissmedic is the drug competent authority.

Japan

A single/integrated review process is in place, similar to the United States, but note that Japan does not follow US process for staked-needle Pre Filled Syringes (PFS) which must follow Essential Principals. Additionally, like the European Union, master files are not an available option.

Saudi Arabia / Malaysia

These countries have newer combination product regulations. Malaysia follows the EU approach of a two-step evaluation by a medical device agency (equivalent to the EU’s Notified Bodies) and a drug competent authority. Data required for submission to their MDA is the same as the EU MDD’s Essential Requirements.

China

Some common combination products like Pre-Filled Syringes are not considered to be devices in China. However, new regulations and guidance continue to emerge that cover device-led combination products (e.g., drug eluting stents) but not yet drug delivery systems.

South Korea

Regulatory bodies have shown most interest in regulating staked needles most specifically, requiring a technical file from the manufacturer and in-country metallurgical testing.

Other Countries

Other regions may have varying degrees of interest/regulation for combination products.

What should I consider when developing a global regulatory strategy for my drug delivery device system?

With major markets maturing, there is an increasing interest in global markets as a new growth opportunity. This is leading to more “advanced” presentations of combination products going into  smaller, less developed markets where regulation is not as advanced or harmonized with major markets. If you are ready to join these trendsetters in taking on an international program, it is important to create a global regulatory strategy before taking on the world.

While the above is a deep, dark rabbit hole of a question that can have various answers, depending on the specific product and markets in question, we can share three key, topline considerations for beginning your global regulatory strategy:

1. Prioritize your intended markets to create a global submission sequence. Commercial considerations are significant to the decisions made here, including market size of the indication’s patient population, reference pricing, regulatory acceptability, company location(s), and partners/affiliates.
2. Identify the level of submission harmonization and customization required across the various jurisdictions of your global market. Submission content and regulator expectations can be highly variable from one to the next. Additionally, global harmonization efforts are currently underway among several regulatory authorities and international guidelines are swiftly changing. It is important to stay informed on the ever-changing global regulatory landscape as you develop a strategy that is harmonized and as streamlined as possible.
3. Determine the necessity of leaning on a local external partner/affiliate to take responsibility for product submissions in certain jurisdictions. This is frequently a requirement among several regulatory authorities, particularly among our Asia affiliates like Japan and China. While ultimate responsibility lies with the Pharma company as sponsor, capitalizing on the in-country expertise of partners can smooth out your submission process.

Updated 6/10/2024

What are each of the arms of the FDA responsible for with regard to reviewing drug delivery devices?

When you are submitting combination products to the FDA, it really helps to know what’s going on behind the scenes, starting with understanding how drug delivery device review responsibility is assigned.

In the medical devices,biologics, anddrugs arena, there’s three main centers we deal with:

As defined by 21 CFR 3.2 (m), the Primary Mode of Action (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.

CDRH is the lead center for medical devices, radiological health products, in vitro diagnostics, and device-led combination products (e.g. where the device function is the PMOA). CDER, the Center for Drug Evaluation and Research, regulates over the counter drugs along with prescriptions and biological therapeutics. This includes generic drugs and most drug-led combination products (prefilled syringes, auto injectors, pen injectors, on-body prefilled systems).

While different submission types will go to specific centers, there can be cross-center review situations where reviewers from one center are consulted on a submission in another center. For example, although a drug-led combination product is regulated by CDER under an NDA, BLA or IND, the responsible device division within CDRH will be consulted by CDER to review the device constituent part of the combination product under the submission. Further, if the proposed product is a cross-labeled combination product, two separate regulatory submissions, one to each center responsible for the respective constituent parts, will be necessary to gain approval for the overall combination product. As a result, there are some instances we may encounter when there’s a device reviewed by CDRH with a drug approved concurrently in CDER that come together in the marketplace as an approved combination product. In this unique case, it will be very important to consider how the timelines of the respective parallel submissions will be managed to avoid any outstanding drug or device regulatory issues resulting from not gaining approval the parallel submissions at the same time. Early engagement with the FDA is recommended to proactively plan for parallel cross-labeled combination product submissions.

CBER historically has not dealt as much with combination products, but there is a growing CP area in CBER. They oversee biologics as well as blood and blood products, blood bank devices and screening tests, vaccines, cellular and gene therapies, and allergenics. We are starting to see a lot of unique delivery options for those areas, as well as in CBER’s other areas of tissue and tissue products, xenotransplantation and biologic-led combination products. However, as we are focusing on combination product manufacturers and their maneuvering through the FDA, we will delve deeper below into CDRH and CDER.

CDRH went through a reorganization a few years ago, right before the pandemic. The center used to be separated into a premarket arm, a post market arm, and a surveillance arm…and those three arms didn’t really talk to each other. They were very siloed, with separate management structures, different device groupings, and, frankly, not giving enough emphasis to the important work that surveillance does. Recognizing changing of times and the need to look at the whole picture of the device lifecycle, the center shifted to a total product life cycle model. The result was a large reorganization, during which they integrated these arms for a more wholistic approach, within more focused and specialized device groups. As examples, what used to be General Hospital Branch was  transformed into the Division of Drug Delivery, General Hospital and Human Factors, which includes the General Hospital Team, Injection Team, Infusion Team and Human Factors Team. In Respiratory, the larger team split into multiple teams like Airway Device and Sleep Apnea Devices. In total, seven device category offices were created, with an 8^th, the Office of Radiological Health forming a few years later, separating radiological devices from OHT7.

Updated 6/14/2024

How are each of the arms of the FDA structured with regard to reviewing drug delivery devices?

It is important to have basic knowledge of who does what within each delivery device-related FDA arm and to take note of some existing nuances to help you communicate better with reviewers, tailor your submissions with specific device review strategies in mind, and plan for efficient but realistic review timelines.

Within each office, there’s reviewers that handle premarket, post-market and surveillance, trained on processes across the total product life cycle. In order to give that perspective, now, as they review both premarket and post-market applications, one of the key improvements is that when you have a reviewer looking at something on the premarket side, they may start asking questions about the quality system. They may start anticipating how are you going to deal with CAPAs when you have a failure in the field. How is that going to feed back into you post-market design control activities? Likewise, when you get your inspection reports reviewed, you are now going to have reviewers that may have more experience on the premarket side, who may better adjudicate whether a post-market action really does require a regulatory submission. This also allows for better surveillance and a more collaborative environment with the agency to balance premarket and post-market needs.  We all know you don’t just send something into the field and then it stays static for the rest of its life. So, the new idea of CDRH is a big emphasis on quality management systems that drive through the entire product life cycle.

Each one of these offices has its own hierarchy, which is important to understand so you know who you’re communicating with, where they fall in this management structure, and who makes which decisions.

At the top level, you have an office director who is in charge of the entire office. Under them there’s four different positions: a deputy director, an assistant director, an assistant director of professional development, and a clinical deputy director. The deputy director and assistant director, for the most part, serve a similar function. The two other top roles in the office hierarchy have more specialized functions.

The clinical deputy director, generally an MD, oversees the clinical aspects of any investigation – any device – that has high-profile clinical applications. This director also acts as a supervisor (but not direct manager) for the medical officers in each division, with the ultimate goal of ensuring clinical consistency across the divisions within that office. And, in a more recently implemented position, the assistant director of professional development works with reviewers on mapping out their career paths, coordinating conference speaking engagements, and facilitating educational opportunities. 

These four positions are supported by the administrative staff and signals coordinator, who in turn also services all of the divisions under this office director team. The signals coordinator identifies post-market activity for surveillance, usually flagged by a reviewer or external observer raising an issue, such as seeing many adverse events for a certain product that are all related to one failure mode. When brought up to the signal coordinator, the signal coordinator initiates an internal process for evaluating that concern for potential elevation to public communication or even product recall.

Each office has about three or four different divisions. In the OPEQ example shown below, there are three.

.As you can see in the above visual, the Office of Health Technology 3 within OPEQ at CDRH has three divisions of Health Technology: 3A, 3B, and 3C. Each division is responsible for specific device categories, creating specialists in those areas. Why not name the divisions after the device groupings? The structural planning team at the FDA was wise enough to know that in this ever-changing and constantly growing health technology world, the needs for device category coverage may change in any one division. The numeric title allows for consistency of division name so that they can remain nimble in the event of the addition or subtraction of any device categories. At the moment, 3A oversees renal, gastrointestinal, obesity and transplant devices; 3B oversees reproductive, gynecology and urology devices; and, 3C oversees drug delivery and general hospital devices, plus human factors.

The team structure within each division is essentially the same, having one director managing a handful of teams focused on a specific device area within that division. Within that division there is a pool of expert reviewers, some of which are designated signatory authorities who work on reviews, primarily within their own team and specializing in that area. However, each of these specialized teams is trained cross-divisionally to effectively participate in any review that comes into the division, so you may wind up with a renal and transplantation devices team member crossing over to work on an obesity and hepatobiliary devices review depending on submissions coming in and team bandwidth. This allows for resources to shift as demand shifts between device applications.

Each team has its own team lead and assistant director who supervise the work/members of that device team and have signatory authority for the team. They handle resource management jointly, while the team lead takes charge in assisting team members with evaluation for approval or denial of applications as needed and the assistant director is the hiring and firing authority for that team. Following the desire for office fluidity to handle workflow, assistant directors will float to other divisions to lend a hand when another assistant director is on leave or has work overflow.

When you’re looking at signatory authorities, the team lead has limited signatory authority, generally reserved for low profile products or minimal impact regulatory decisions (e.g. clearances/approvals/meeting feedback). However, the majority of decisions are actually signed by the assistant director. Typically, disapprovals or negative recommendations require more levels of signature as do post-market compliance actions. The next level of signatory authority would be the division director, with the office director as final level of signatory authority as needed. For example, for a 510K to be granted clearance, the team lead can sign on behalf of the assistant director (or the assistant director can sign on their own) and call it a day. But, for a disapproval or review determined to be not substantially equivalent, the assistant director and the division director have to sign off on it. Whenever there’s an appeal, it also goes up to the next level. (If the assistant director signed off on your appeal, they appeal to the division director for co-signature. If the division director originally signed off, that goes up to the office director for final determination.)

The pool of talent within each division also includes one or more medical officers who are shared between the teams, based on the specialties. A lot of people think reviewers are mostly engineers, and that is largely the case. However, there are also medical professionals such as nurses (a lot of nurses actually), physicians, pharmacists, chemists, biologists and even the rare virologist (who would usually be housed in CDER). In the medical officer role, you have a lot of people with different backgrounds – though all scientific backgrounds.

CDER is a little bit different than CDRH, as you can see in the chart below, borrowed from the FDA.

The CDER center structure is organized by clinical area, and they have also recently gone through a reorganization to align product areas. So, if you once had the division acronyms memorized, it’s time to study up! (You can always search them up within an abbreviations and acronyms database on the FDA website.) There’s a lot more offices within CDER, with bigger offices than you’re likely to deal with in CDRH. Not only is CDER a bigger center than CDRH, but their structure is also a bit flatter too, 

Within each CDER office there’s lots of divisions. Each division has a director and deputy director, a review staff pool, and typically about two team leads that help supervise that staff. Unlike CDRH, there’s no separate teams within each division. Instead of set teams, there are individual program managers assigned to manage the review submissions, who sit at the office level in an Operations capacity and are doled out among the divisions where workflow requires. These program managers are responsible for the submission’s administrative work and regulatory flow. While they do receive some technical training, they generally do not have technical or scientific backgrounds and cannot provide any technical feedback, which is what the division team members are for (review staff, team leads, deputy director and directory). Meanwhile, signatory authorities stay at the deputy director and director level with zero signatory authority given to team leads or review staff.

Policy management happens back in CDRH, where the OPEQ ‘Super Office’ personnel get involved at the policy-setting level and sit in an office of CDRH “above” the 7 review offices. They are the people developing the policies around 510Ks and balancing safety needs with ensuring that the needs of patients are being met, and typically only get involved in reviews when there is an issue of policy. If a device manufacturer does something that is precedent-setting or brings up a very difficult regulatory science question, the review division may seek advice from somebody in the Super Office. They don’t actually conduct any reviews, including consulting reviews, but they can enter the conversation to provide policy guidance.

[Updated 6/24/2024]

What are the key differences in working with CDER and CDRH?

Below, you will find a table that highlights key differences between CDER and CDRH, to help paint a picture of who you are dealing with and how they deal with you.

The types of submissions accepted by CDER and CDRH are markedly different, as you can see in the below listings. Meanwhile, CBER, uniquely receives all of the types of submissions that CDER and CDRH accept due to the nature of the products under their purview.

CDER Submissions

• NDA: 505(b)1; 505(b)2; ANDA 505(j)
• BLA (351): Biosimilars
• NDA/BLA Supplements: Prior Approval Supplement (PAS), CBE 30 Days, CBE, Labeling
• IND: Clinical Study, Meeting Request Type A/B/C

CDRH Submissions

• Q-Submissions (guidance links): Pre-Submissions; Submission Issue Requests; Information Requests; Special Pre-Submission Programs
• 510(k) – Traditional/Abbreviated ; Special
• De Novo
• 513(g)  (link to guidance)
• PMA – Original; 180-Day Supplement; 30-Day Notice; Real Time Supplement; Annual Report; CBE Supplement
• IDE – Original; Amendments; Supplements; Reports
• Special Programs: Breakthrough; STeP; etc

The submission timeline for clinical studies is 30 days regardless of the center. However, premarket applications vary greatly between centers and within them, depending on the complexity of the submission. Within CDRH, submission timelines range between 30 to 180 days; within CDER, they are typically 6 to 10 months, with a possible “priority review” within four months. 

Another variable between offices is the type of meeting categories on offer. When approaching the FDA for a meeting, the type of product will dictate which center. Then, the type of feedback needed will dictate the type of meeting to be requested. The below table maps out comparable meetings that can be requested from CDER and CDRH, along with timings of meeting packages and actual meetings.

It is important to note the timings for when your Meeting Package must be provided. For CDRH, you must submit all of the relevant information for the meeting request at the time of making the request, without opportunity to add to the package later on. Whereas, with CDER, you can make the request then have between 2 to 6 weeks to get your ducks in a row.

Depending on with which center you deal, there are certain types of feedback/meetings that are unavailable. CDER’s Type B Meeting, during which the center will pre-review submissions at various stages of development, has no equivalent at CDRH – they do not do pre-reviews. However, CDRH does provide Informational Meetings, which are not generally available in CDER (though some divisions within CDER will entertain informational meetings).

The last unique difference to note about meeting types is that CDER may actually not provide a meeting at all. This center has the authority to convert meeting requests into WRO’s, or written response only, instead of granting a meeting. 

[Updated 7/1/2024]

What is the practical submission timeline that I should plan for?

Let’s start with a tip: Submit on a Monday! 180 days is not actually 180 days when you take weekends and holidays into consideration. Starting your submission with a full work week maximizes the workdays your reviewer has to make a decision. And, that’s only the tip of the iceberg when it comes to what might pull your reviewer away from actively reviewing your submission, or pull your submission away from your reviewer, during their allotted submission timeline.

What will help you really understand how long the review process will take, and how best to maneuver through it, is to get to know the process flow, which is different between CDER and CDRH.

We have shown previously that for both CDRH and CDER, clinical study submission timelines are 30 days, but other submissions can range from 30 to 180 days with CDRH and from 6 to 10 months with CDER. That may feel like a long review time to sit and wait, but as you can see in the above flow chart, the process has many steps and many contributing players that reduce the actual time your lead reviewer has with your submission. With potentially a dozen or two submissions on their desk at any time, while these timeframes can feel excessive in “industry time” they can feel excessively tight in “reviewer time.” In the above flow charts, the time your lead reviewer actually has with your submission is indicated by the light blue bars. 

In the case of CDRH reviews, the review may be put on hold during each phase of their review, during which time you, as the sponsor, will have an allotted timeframe (not counted in the FDA days to review) to address the review team’s questions or concerns (also known as deficiencies). So, what may technically be a 30, 90, or 180 day clock, may actually take up to (and even over) a year from initial submission to final decision. The tradeoff is there’s usually more opportunity to address any major the concerns the Agency raises during the review cycle and there’s also clearer expectations around what point during the review cycle you will receive that feedback. The review team is also at liberty to interactively request information during their review, while their review clock is running, but in many instances such interactive requests are limited to more straightforward clarifying questions or requests for (hopefully) already existing data.

In the case of CDER, there are no formal hold periods as part of the review process, except at the filing stage if they refuse to accept your NDA, BLA or ANDA submission. Therefore, CDER reviews are much more interactive, with the possibility of receiving an information request email from the review team at almost any point of the review. Additionally, while there are established periods/phases of the review cycle – with the mid-cycle being the most probable point at which you will receive feedback on the review team’s major concerns with your submission – there are no guarantees that you will receive feedback from all review areas at this timepoint and it does not minimize the possibility of major concerns being raised for the first time after this point. This is particularly true of any potential feedback coming from the CDRH consultant who relies heavily on the CDER regulatory project manager (RPM) to first issue the consult in a timely fashion and to then communicate the major review milestones to allow for timely feedback. In fact, CDRH will not even be aware that there is a review required for the device constituent of a combination product until CDER sends the submission over to CDRH via the intercenter consult process. 

Keep in mind that there are also several administrative tasks involved with arranging for a consult, as well as documentation tasks involved with incorporating a consulting agent’s work, which takes additional time away from the reviewer actually reviewing and pushing your submission forward. In short, due to many collaborative and administrative steps in the process that takes timeline control out of your lead reviewer’s hands, they are most likely in a mad scramble to meet deadlines while you are tapping your foot in impatient wonder of why it takes so long to read your submission and give feedback. No need to pity your lead reviewer, but you can help them and your own situation by being very clear, prepared, quick, and direct in your interactions. There is not a lot of time for back and forth with all that is happening behind the scenes at the FDA to ensure your submission review is thoroughly vetted.

[Updated 7/9/2024]

How does the FDA review process work?

The above flow chart breaks down the previously shown comparison of timelines flowchart for a CDER or CBER review process (they are basically interchangeable), after a submission review has been accepted. Before the FDA begins a substantive submission review in earnest, there are many determinations, consult requests, and administrative tasks that need to occur to line up the most appropriate team to review the submission. The more complicated and more innovative the combination product submission, the longer this initial lead-assigning and team-building process can take, and the larger the team might become to help cover unchartered territory. On the other hand, the more simple and common the combination product submitted, the smaller the FDA footprint. In fact, in some cases, like for pre-filled syringes, a consult to CDRH may not be needed; the lead review center can pretty much review the device by established templates, leaving CDRH’s team available for more complex and precedence-setting  situations.

During the review, there is informal and trackable dialogue/collaboration between centers and between lead reviewers and expert consultants. There is also back and forth with the regulatory submission sponsor, who has submitted the combination product for review, to address questions and deficiencies in the submission that must be rectified to move the review process forward. This back and forth is called the Interactive Review Process.

Unlike the internal back and forth within the agency, the Interactive Review Process between FDA and sponsor is formalized because every interaction between the NDA sponsor and the agency has to be tracked and added to the NDA file by the Regulatory Program Manager (RPM). That makes reaching out with a quick phone call or email out of the question. Instead, the lead reviewer must draft a request for information, submit it to the RPM, who in turn logs it into the document control center and gets it out to the sponsor in a formal letter request. The RPM then also acts as intermediary and documentarian for the sponsor’s response to the reviewer. Playing telephone isn’t the fastest way to ask a question, but it is a crucial step within CDER and CBER to make sure the NDA file is complete. CDRH does not have this requirement. Instead, their reviewers hold the responsibility of uploading information that needs to be documented into their document library. And, there is more flexibility in how to engage with the sponsor, with the lead review at liberty to communicate through preferred means, whether formally in the milestone communications (e.g. AINN letters), interactively via email, or even with a phone call or informal teleconference.

[Updated 7/15/2024]

What is my Reviewer doing in the review?

You hear people talk about review memos, but what’s actually going on? The Reviewer strategy is the same for device or device constituent. It’s the same thought process, just with certain elements applying over others.

It begins with an administrative review, where a Reviewer from each review area for the team (which usually includes the device consultant) evaluates the submission for administrative completion.

• In CDER/CBER this is known as the filing stage of the review.
• In CDRH, for 510(k)’s this is known as the RTA phase, which is now known as the Technical Screening Phase for the new eSTAR program (eSTAR is the new required submission method for all 510(k) submissions).
• PMAs in CDRH are similar to CDER/CBER submissions in that they also have a filing review (albeit with a 45 day clock rather than the 60 days for CDER/CBER submissions).

To help with this administrative review, Reviewers utilize a high-level checklist that confirms specific sections/contents have been included in the submission. These checklists are not product-specific and are more focused on ensuring the regulatory elements have been addressed in the submission contents.

Once the review has been found to be administratively complete, the substantive review phase follows. For CDER/CBER submissions, what this means for your device consultant is a walk-through of your submission contents (as it relates to the device constituent of the combination product) for the necessary elements to support a demonstration of safety and effectiveness (S&E). To aid in the walk-through, Reviewers follow a memo template that is specific to device-type or submission-type, which helps them prioritize their focus on what elements of a submission really matter for making that S&E determination. For example, relevant memo sections will provide perspective on important elements like: how it’s used, how it’s communicated, Human Factors considerations, reprocessing, sterility, shelf cleaning, biocompatibility, software, firmware, EMC, etc. (basically your 60601 suite). Note that not every device type has its own code due to the level of innovation and product niches in the industry, and there may be some variances to what needs to be reviewed based on what the specific intended use is (including use environment, medication criticality and user population).

Within the substantive review phase, the Reviewer will go through each section using guides (including standards, FDA guidance documents, USP requirements, regulations, etc.) and checklists relevant to that section. They still have to review the information and do the critical thinking, particularly when weighing determinations on whether the benefit outweighs any identified risk. The memo template helps ensure there’s consistency in the questions asked for the same types of products. These templates are continually being improved and made to be “smarter” (embedding macros and links to prompt certain precedence/reference checks), with new iterations emerging as the industry continues to change and innovate.

A key focus as they go through the template sections surrounds the design control elements – particularly your verification and validation data. During the design control review, they are looking at submission elements like safety assurance cases, risk management documentation, Human Factors validation data, design verification testing, stability testing and benefit risk assessments. They will also take a look at your Control Strategy – how you are controlling EPRs through the manufacturing process. This is looked at in a larger scale during your Quality review, should a full Quality System assessment be a specific element of their review.

Not all products will require a quality system review, as CDER and CDRH have reached internal agreements as to what products or treatment indications are critical enough to warrant a full QS review.

Whether initially required for submission review or not, you still have to install a Quality Management System and go through the Risk Analysis process. While current FDA resource limitations and prioritization may not always require these items in submission, this could change and, regardless of submission requirements, both elements are still required by the regulations. And, there is always the possibility that post market signals hit their radar and create a later need for review.

Note that the Reviewer is not working in a vacuum. For CDER/CBER submssions, at a minimum, there are three meetings with a larger cross-disciplinary team.

1. First, there is a filing meeting involving every single review discipline, including CDRH, at the onset of the submission review.
2. Then there is always a mid-cycle meeting with the same disciplines.
3. Finally, there will be a late cycle meeting prior to official approval designed specifically for discussion of any approvability for all the disciplines, including CDRH and higher ups in CDER management.
4. In addition to these team-wide meetings, there are usually several labeling meetings near the end of the review cycle to align on the final product labeling language.
5. Beyond these standard meetings, certain CDER divisions tend to be more meeting-happy than others, and will set monthly team check ins.
6. There is often one-on-one meetings with specialists to collaborate on certain areas. One, in particular, that happens more than others is Human Factors.

[updated 7/22/24]

What training and tools does my Reviewer have at their disposal?

A big internal push at the FDA is to promote cross-divisional consistency and efficiency. The device-specific review templates previously mentioned are a step in the right direction toward creating consistency in the scope of a review, and they are a very useful tool to prepare Reviewers for the review of your product. To further the cause, there’s a big effort for digital transformation at the agency that can create more internal databases and metadata to allow for review cross-checking. As data systems grow, and intercenter consult and collaboration mechanisms are improved, you will see more and more consistency across reviews, divisions, and product categories.

Something to keep in mind, which might surprise you given the authority of the FDA, is that many  reviewers are straight out of college or academia (but do have advanced degrees, particularly in CDER). Many reviewers when starting at the FDA don’t have any industry experience, resulting in very theoretical knowledge of the medical device development process and cGMPs. Further, many had previously never heard of combination products and are learning as they go, or as they say, building the plane while they’re learning to fly it. Because of this, there can be the tendency to treat things like an academic exercise, directing the entire review process black and white to the regulations, with little nuance or understanding of grey areas. If you find that is the case, try tailoring your questions, your feedback, and your discussions to address the specific elements of the reviewer’s interests without derailing down rabbit holes.

When the FDA gets a new hire, they begin by reading all of the guidance documents and standards that are applicable to the product type for each new submission the new hire will be reviewing. The  reviewer learns to live by them because, as a regulatory agency with legal implications, guidance documents and standards are relied on heavily as a consistent resource to interpret the regulations. When a submitting company is making a substantially equivalent argument in a 510(k), reviewers are comparing it to something that has been previously cleared, the predicate device(s). Even in PMAs, and CDER/CBER submission,  the FDA relies heavily on precedent to help inform their understanding of the benefit/risk profile of a particular product under a submission. Having previous review rulings publicly available, one strategy for pushing your submission through is making your own case based on precedent. That said, be mindful not to argue a precedent that was clearly made by mistake and does not follow guidance and standards or have a logical argument for non-adherence. It can often open the door for deeper digging into your submission and added responsibilities in addressing previously unconsidered or unforeseen risks.

In CDRH, all TPLC reviewers – engineers and medical officers alike – are expected to have a “tier one” basic level of knowledge across all the different disciplines, which is facilitated through a FDA internal training/certification program to get people caught up in their individual knowledge gaps. When your mechanical engineer reviewer came to the FDA, they probably didn’t know a lot about biocompatibility or sterility. Meanwhile, your microbiologist may be very familiar with those topics, but maybe doesn’t know some of the electromechanical aspects of the system. With this wide variety of specialties, you see a lot of peer-to-peer training and specialty area bootcamps to get the entire team to a base knowledge level across specialties. What this does mean, though, is depending on the experience of the reviewer, they may or may not be fully familiar with all aspects…yet…when your review lands on their desk. Therefore, it is a good idea to provide a clear, concise and scientifically sound presentation of your submission contents, in such a way that anyone with a foundational knowledge of regulatory submissions can easily follow and understand.

With the FDA’s new total lifecycle process structure and cross-process internal training, you can expect both pre- and postmarket questions from the same assigned reviewer. Occasionally, you will be told that a subject matter expert is stepping in to provide a particular consult (biocompatibility, sterility, etc.). These specialists will join to consult if a lead viewer has a specialty area knowledge gap or if a complex review case exceeds their basic level of understanding. Some of them are lead reviewers themselves, lending support, while others have enough work (such as software reviewers these days) to only focus on the software portion of any review, never having the general time to take the lead. These consultants can come from other  divisions or offices as well. For example, consultants often are pulled from the Office of Science and Engineering Laboratories, a research arm of CDRH. So, when CDER is reviewing a combination product, the CDRH employee is serving as a consultant to CDER, and you may hear them referred to as the CDRH consultant or the device consultant. Typical areas that might seek consult these days would be clinical, sterility, biocompatibility, software, cyber statistics, electrical engineering, MRI compatibility, and human factors. These are review areas where the situations are likely more complex than the tier one knowledge base training affords.

Another important tool to mention is comparable human resources. For various reasons, to the chagrin of the submitting company, a Reviewer may need to be replaced. It can happen for personal reasons, workload shifts for certain specialties, or even – for a particular category of employees called Public Health Service Officers (uniformed federal service officeswho can get deployed during public health emergencies or natural disasters) – situations where, for example, an engineer gets deployed after a hurricane to help manage logistics or a nurse/pharmacist gets deployed for COVID.  The latter can happen with 24 hours’ notice, mid-review, and managers need to shift around all their work. While it presents challenges in attempts to maintain consistency throughout the review process, the FDA is ready to adapt and has experience – especially in the last handful of years – in moving workloads between Reviewers to accommodate external needs and, in cases, the work of everyday heroes.

[Updated 7/29/24]

How does decision-making and dispute resolution work at the FDA?

When it comes to decision-making, as mentioned earlier where we discussed the hierarchies of the various FDA centers, there’s different levels of signatory authority. For example, in CDRH reviews, it starts with the Team Lead, then moves up to the Assistant Director, Division Director, and Office Director. However, the buck does not always stop there…

When you have precedent-setting filings or policy issues, they may also need to go through a level of decision-making approval with the Policy Division. Recently, in the newer product category of digital health, there are many non-precedented topics that the Digital Health Program would comment on that won’t always concur with the Review Division. Generally, the Review Division gets to make the ultimate decision, but the Policy Group has the responsibility of steering them in a direction that aligns with the way they’re intending to execute the policy.

What happens when there are internal disputes? When a manager does not agree with their subordinate’s decision on a filing, there is first a round of discussion in an attempt to sway opinions one way or the other. If the disagreement persists, it is the role of the manager to write a memo with their rationale for overriding the subordinate’s decision and send it up the flagpole to the next level of signatory authority. This seems a simple method of checks and balances to ensure the proper verdict is given, but as a submitting company, you should be aware of the nuances surrounding the of the decision-making process.

• For one, sending a memo of disagreement up the chain for next-level concurrence takes time that no one at the FDA has, and also holds up submissions. As a result, at times, compromise is made despite what a manager thinks is the right course of action simply because of bandwidth and time constraints.  
• Another impediment to the decision-making process is politics. There is often pressure from “above” (and from industry) to meet the review timeline goals established both internally and externally (in the form of MDUFA/PDUFA/GDUFA) commitments. This makes the time of substantive dialogue on review decisions, particularly when the signatory authority disagrees, severely limited. This oftentimes leads reviewers and signatory authorities in precarious positions, having to decide whether what they believe is valid enough and poses a sufficiently significant risk to public health/safety to hold up a review decision, or to let it go, understanding that (1) the benefit outweighs the risk and (2) there are established policies and post-market procedures in place, in the event that the risk they identified is realized as patient harm in the field. This, in essence, is the foundation of the FDA’s benefit/risk decisions.  

What happens when there are clinical concerns or a need to address clinical interpretations? At times, aside from bringing in upper management, Reviewers may bring in a clinician for a resolution. At other times, other centers will get involved. Technically, CDER is the ultimate decision-maker when it comes to drug-led Combination Products. However, when there are cross-center or division issues, any party can go to the Office of Combination Products to step in as mediator and take a neutral look in an effort to iron things out, reset expectations, and prioritize concerns.

What about if you, as the submission sponsor, have a dispute that needs resolution? How decisions are formed can impact the product and your business, so you should know that as an external person, it is valid to bring any concerns you have up and even – eventually – request the Office of Combination Product get involved. That office can act as a mediator and help move things through that get stuck in Management and Reviewer dispute. In particularly sticky situations, it may be to the company’s benefit to contact the office of the Ombudsman in CDER or CDRH. These offices are specifically tasked with investigating and mediating disputes raised by companies regarding reviews handled by the centers. This is often a last resort after repeated efforts to collaborate with your review team have fallen short. Such an approach is not without risks as it may place added strain on the relationship between the company and the review division, making future interactions on submissions/supplements/meetings a bit uncomfortable for both parties. It should also be noted that flagging reviews to the ombudsman should not be executed solely due to not being happy with the review team’s decision, but rather when there are specific concerns of inconsistency or departure from policy, guidance or precedence from the review team.

[Updated 8/5/2024]

How can I maintain a strong relationship with the FDA?

Understanding your FDA Reviewer’s position, workload, knowledgebase, needs, and responsibilities is a solid first step in establishing a good long-term relationship with your regulatory body. Taking this into account during your interactions is the next step to locking in that good relationship. Your FDA Reviewer is in the business of pushing through approval-worthy combination products, not grudge-holding, and human nature requires a level of respect and understanding in the working relationship. So, some tips for getting the most out of your interactions with the FDA:

1. As mentioned before, guidance and standards are the bible of the FDA. Pushing arguments grounded on precedents that are based on mistaken interpretations of applicable guidance and standards puts your Reviewer in the precarious position of having to approve something based simpley on precedence versus approving or denying a filing based on guidance and standards and a solid and scientifically sound demonstration that (1) the product is reasonably safe and effective and (2) the benefits outweigh the risks of any uncertainties.
2. With guidance and standards as the key checklists (their security, if you will) for your Reviewers assessment of your product filing, you can make their life easier by not just referencing applied guidance and standards but calling out how you meet the standards line by line using complimentary language. This really spells out your compliance and makes the submission fool-proof for them and a faster and smoother review for your timing’s sake. For novel products in particular, it is beneficial to specifically define the benefit/risk profile of the product, tying it to clinical data and other scientific evidence to support your conclusions.
3. While it is your valid prerogative to externally escalate issues you have with your filing, it is never good form to immediately escalate something beyond your initial Reviewer. Despite tight timelines and budget concerns, voice your concerns with your Reviewer or Regulatory Project Manager, then at most, start with their direct manager before tapping someone multiple layers above them. There are many layers before you get to the top, and you should use them in pecking order to avoid ruffling feathers.
4. Civility means everything. While this is a business endeavor, Reviewers are people with emotions. Not only does that matter in itself, but from a self-serving perspective, while they won’t hold up a filing due to hurt feelings, they do have the prerogative to decide things like how much time is allotted for you to respond to questions or how much of their own time they devote to providing helpful guidance versus simply reviewing for a yes or a no. Reviewers also talk…expect that insulted Reviewers not only remember your name and your company’s name, but that they have shared their opinions with FDA colleagues who may be assigned to your next filing. So, as your mom would tell you…”Check your tone.”
5. While most of your transactions and communications are documented through FDA process, it is in your best interest to ensure that you are always documenting everything discussed with the FDA. Sometimes you may have an informal phone call that doesn’t get logged into the FDA system, and the minutes you take can be the evidence of that conversation and sway the future of your filing. This is also helpful when there is a resource change at the FDA and you need to get your new contact up to speed without taking two steps back.

[Updated 8/13/2024]

What are some best practices for FDA meetings/communication that I should follow?

1. Consider how you focus questions and to which personnel they are directed to gain the feedback you seek.
   • Be specific and direct about your topic and particular question.
   • Identify the relevant document areas within which your reviewer should look.
   • Engage Reviewers, not Managers, for most topics.
   • Engage Managers when you are trying to overturn a Reviewer’s opinion or when you feel something is overly burdensome.
2. Questions are likely to have multiple facets, so make it clear what is being sought. For example:
   • Does Agency agree with dose accuracy requirements?
   • Clinical – Does Agency agree that the results of the Phase II clinical trial support the proposed dosing regime?
   • CMC – Does Agency agree that the formulation of the product aligns to the requirements challenged during the Phase III clinical trial?
   • Bioequivalence – Does Agency agree that the results of the Phase III clinical trial can support the proposed bioequivalent regime in the future BLA?
   • Does Agency agree that the methods described support the proposed dose accuracy requirements at the described intended use?
3. Never ask a question to which you do not want the answer.
4. Read the room. If the FDA agrees or doesn’t have any feedback…move on.
5. Never offer up a solution you are not prepared to execute upon.
6. Use phrasing like “what is THE AGENCY’s opinion on XYZ” instead of “what is YOUR opinion on XYZ.”
7. There is a right way to attempt to get feedback on your intended approach: “I understand this might be a review issue, but does the approach and methodology align with the Agency’s expectations?”
8. Designate who will talk to which topics. We recommend a mix of regulatory affairs and development team members. While consultants can be there to make sure communications run smoothly, try to limit any consultant’s speaking role. The FDA wants to hear directly from you.
9. The FDA likes to hear from subject matter experts, so be prepared to have those questions ask questions and engage.
10. Prioritize what you want out of your meetings with the FDA.
    • There are often more topics than can be discussed in a 1 hr meeting, as an organization go in with your top 3 specific questions you want answered and then prioritize the remaining.
    • You drive the meeting and can decide the order with which you want to focus the meeting, it is YOUR meeting
    • Have back up pathways that you would be amendable to pursuing – for example, we propose testing this way, but we could do it another way. Prioritize what you as a company would prefer doing first.
11. Be conscious of moving FDA meetings along so you can touch on all of your priority topics.
    • Certain topics have a tendency to lead you down a tangent – understand when to walk away
    • Reviewers just like scientists/engineers can get into the weeds, know when to say ‘thank you, we appreciate the insight and will take that back to the team as we develop our response’
    • Back to prioritization, when do you want to cut off the conversation on a topic? Designate someone who can make that call and step in
    • Always state that you will take something into consideration, not that you 100% agree or will do exactly what they suggest. Flatter but don’t commit.
12. Understand post-meeting follow up procedure.
    • You may request that specific feedback be provided in response to the meeting minutes or in a follow up email
    • Don’t expect the requested feedback to be delivered promptly. Even if they commit during the meeting to a particular timeframe, something else may come up which delays their ability to respond.
    • Understand that follow up conversations are likely to be deferred to a Type C Meeting.

[Updated 4/30/2025]

Questions about Risk Management

What risks do I need to manage for a combination product program?

When we talk about risk, we are in essence discussing the identified potential hazards and hazardous situations involved using a combination product, and the subsequent calculation of the probability of a specific occurrence of harm and the severity (measure of the possible consequences of a hazard) of that harm within the likely hazardous situations.

Risk management – the systematic application of management policies, procedures and practices to the tasks of analyzing, evaluating, controlling and monitoring risk (ISO 14971:2019) – is an integral part of a combination product’s quality management system. Companies who develop drug-device combination products use ISO 14971 and TIR 24971 as the gold standard for guiding their risk management policies and procedures relating to

1. Device Use
2. Device Manufacturing/Process
3. Device Design

A successful risk management strategy answers the questions:

• Can risk be reduced?
• Is the level of risk acceptable?
• What controls are necessary to mitigate risk?
• Does risk continue to remain controlled and acceptable?

An effective risk management program actively collects and analyzes the following data to assess risk for both initial assessment:

• Use Failure Mode and Effects Analysis (FMEA) – identify potential use error and use-related risks through task analysis (use scenarios and user tasks)
• System Failure Mode and Effects Analysis (FMEA) – identify failure modes, causes, effects and potential risk controls of system components/devices, packaging and labeling
• Design Failure Mode and Effects Analysis (FMEA) – identify failure modes, causes, effects and potential risk controls of design-level functions of components and devices
• Process Failure Mode and Effects Analysis (FMEA) – identify failure modes, causes, effects and potential risk controls of the manufacturing process steps for device, packaging and labeling
• Hazard Analysis – a system-level, top-down calculation and assessment of risk, utilizing information gathered in FMEAs, for each hazardous situation associated with failures and misuse of the combination product and interface to the drug constituent

…and lifecycle maintenance:

• Post market data (complaints)
  • Hazardous situations
  • Harms
  • Occurrence rates

Examples of FMEA and Hazard Analysis risks are below.

For more information on how to calculate risk, visit our article “Risk Management Assessment For Combination Products.”

[Updated 5/8/2025]

When does device constituent risk management begin?

For a combination product program, you begin assessing risk when you make your first decisions about the device you select for the drug delivery system. The initial choice of whether to go with an off-the-shelf product (not that any drug delivery device can be truly off-the-shelf from a regulatory standpoint), a customized platform device, or a novel device will decide your risk starting point. Weighing the risk trade off of developing a novel device to be 100% compatible with your drug and primary container against the commercial and regulatory risk that comes with a less defined and likely slower pathway to market for that level of customization will be one of your first device-related risk tolerance considerations.

Whether it is more prudent to make an off-the-shelf device with limited changes work or whether there is a path to successfully de-risking a novel device approach will surface in the calculations of an effective risk management assessment.

[Updated 5/15/2025]

How can I assess the project risk of using a novel device constituent vs. an off-the-shelf device constituent?

Based on both knowns and unknowns of each device constituent option, a risk analysis is performed to identify potential hazards, the likelihood of hazardous situations occurring, the potential associated harms, and the severity of those harms for each option on the table.

Suttons Creek assesses program risks from both a timeline and financial impact to the overall program. The probability of the risk occurring is reviewed according to the probability of the event occurring, considering that multiple events may be required for an outcome to happen. A project risk heat map is an effective tool for mapping out ranked risks and visualizing their impact on your project. See below for an example heat map.

[Updated 5/30/2025]

How does Human Factors relate to Risk Management?

Per FDA Guidance: Applying Human Factors and Usability Engineering to Medical Devices, “the application of knowledge about human behavior, abilities, limitations, and other characteristics of medical device users to the design of medical devices including mechanical and software driven user interfaces, systems, tasks, user documentation, and user training to enhance and demonstrate safe and effective use. Human factors engineering and usability engineering can be considered to be synonymous.” This guidance, along with IEC 623366-1 Application of Usability Engineering to Medical Devices are the goal standard of Human Factors Engineering (HFE) and Usability Engineering (UE) in medical devices.

The purpose of HFE and UE is to ensure that the device user interface has been designed such that use errors that occur during the use of the device which could cause harm or degrade medical treatment are either eliminated or reduced to the extent possible. The HFE/UE process will inform the Use FMEA (discussed above) with regard to identification of potential use error and use-related risks through task analysis (use scenarios and user tasks) and potential controls to support mitigation of these risks.

Figure 3 [Addressing Use-Related Hazards in Risk Management] from section 4.2 Risk Management of the FDA Guidance: Applying Human Factors and Usability Engineering to Medical Devices provides a clear depiction of the pat HFE and UE play in risk management. It is important to note that the FDA does not consider probability when assessing usability risks, so your assessment should not incorporate probability as a justification of risks.

[Updated 6/12/2025]

Questions about evaluating delivery devices for your drug/biologic program

For biopharma leaders guiding programs through Phase  2, the decision to develop a combination product—a therapeutic that integrates a drug or biologic with a delivery device or digital component—is no longer just a downstream operational detail. It’s a pivotal inflection point that affects your regulatory trajectory, market access potential, and long-term valuation.

Yet many teams begin making device-related decisions reactively or in silos—without the cross-functional alignment or technical foresight required for success. As a result, promising programs encounter unnecessary delays, budget overruns, or missed differentiation opportunities.

As a decision-maker, the two biggest questions to start with are: “What are  the most important strategic questions I should be asking about combination products at early phases of clinical development (e.g. Phase 1 into Phase 2)?” and “What does it look like to get those answers right?” This article will continue to delve into that for you…starting with whether a combination product is even a good idea to pursue.

When is the right time to select a drug delivery device?

Adding a delivery device to a drug asset can be done at any stage of drug development, based on your particular needs, and with their own unique benefits and downfalls.

• Pre-Clinical/Phase 1: Making an early decision to pursue a combination product and beginning strategic planning at the outset of drug development is the most ideal time to begin the pursuit of a combination product from a financial perspective. Knowing your device pathway from the beginning of the process allows for proper resourcing, budgeting, and process alignment for device selection/development, regulatory documentation, quality management, risk management, and commercial planning/execution. However, the need for a combination product is not always a known or a priority this early on, so not everyone can capitalize on this option.
• Phase 2: More often, we see companies make an additive adaptation decision during Phase 2 Clinical Development as a second route of administration. Starting device decision-making at this stage requires updated budgets and alignment with existing drug development timelines. Without a strategic foundation being set early-on, this start timing will likely double or triple the costs of developing a combination product.
• Filing Addition (Phase 3/BLA Submission): At this stage of the game, adding a device constituent to a drug will delay BLA filing. Your team will need to implement a clinical bridge strategy that may include repeating or supplementing clinical phases, in addition to new human factors validations and a new stability program. This is the most expensive time to start a combination product…and is not recommended.
• Lifecycle Management Change: Adding a delivery device to an existing drug product that is approved and on the market as a way to address commercial and patient needs is a commonly seen timing for introducing a combination product. It will likely be more costly than initiating the project during Pre-Clinical/Phase 1, but less expensive than making it an additive adaption during Phase 2.

[Updated 6/26/2025]

Is a Combination Product the Right Strategic Fit—Or a Distraction?

While it is potentially easier and faster to provide a drug in a vial, never assume that one does NOT need a combination product. While not all situations call for a combination product, this decision should be thoroughly vetted from multiple perspectives before blazing ahead with a decision that may be difficult to change later.

From an executive standpoint, this calls for discipline: ensure your team has done a rigorous assessment of the strategic rationale behind a device component, including:

• Clinical necessity: Is there something about your molecule—particularly its route of administration, but also considering its dose volume and frequency—that requires specialized delivery to be viable or competitive?
• Patient impact: Will a device materially improve the patient’s experience, safety, or adherence?
• Commercial relevance: Can the delivery solution be used to strengthen your market position, gain access advantages, or expand therapeutic reach? Or, is a delivery solution necessary to be competitive with the current market or other therapies that may also be in development?

A combination product should be pursued only when it enhances the value of the therapy—not simply because it can be pursued (i.e. just because one can do something doesn’t mean one should). Sophisticated leadership resists the impulse to jump on the bandwagon and grounds the decision in long-term value creation.

For example, a startup with a subcutaneous injectable targeting chronic conditions might benefit enormously from an autoinjector that simplifies weekly at-home use. But a company developing an IV oncology agent delivered by professionals in-clinic may not gain much from a custom device—and could lose valuable time and money pursuing one.

So, how do you know if a combination product is right for your drug program?

Let’s go back to the “beginning” and go over the drivers for a pharmaceutical company to develop a combination product that includes a drug delivery device.

1. Lifecycle Management: Introducing a self-administered combination product is a way to evolve your product, expand your brand, and extend your patent.
2. Competitive Advantage: Launching a combination product can preserve or expand your market share if you can be first to market, provide beneficial innovation, offer a cost-effective alternative to existing market products, or serve ignored markets.
3. Patient Focus: A combination product can address the needs of patients that want or need the convenience of at-home, self-administered treatment and it can improve access to the drug/therapy as well as comfort during administration.
4. Adherence: Functionalities can be applied to drug delivery devices that support patient adherence through digital monitoring and indicators that demonstrate the user has fulfilled administration requirements.

Companies considering the above drivers are not, per say, looking for combination products. They are looking for a solution to a problem and, sometimes, a combination product is the answer. To determine whether a drug delivery device is a viable answer, we have outlined some decision-supporting questions.

• Do I have any drug formulation issues (i.e., drug is unstable in liquid form or that the drug requires a high dose that cannot be accommodated in the device even in its highest concentration) that would prevent us from using a drug delivery device?
• Are options for this device constituent compatible with my drug’s viscosity, dose volume and concentration?
• Is my drug compatible with the necessary device sub-assembly requirements (such as packaging, shipping, material handling, controlled temperature storage, component shelf-life, material requirements/specifications) and final assembly requirements (such as filled primary container specification, orientation and WIP packaging for assembly, final assembly process control and defect detection/inspection, device labeling, UDI, and sterilization)?
• Will the cost of good sold (COGS) for this combination product price me out of the market or be considerably more than other available options?
• Do we have the time and budget for the additional development studies and regulatory approvals necessary to develop this combination product?
• Does the drug have significant side effects and a REMS program requiring prescription, dispensing and administration through a list of trained HCPs?
• Are my patient populations capable of safe, effective, and adherent self-administration with this drug delivery device?
• Are there any effects to patient benefits/costs, physician payment, or payor considerations that would negatively impact our ability to market this combination product?
• Will our product differentiate us enough in the market to gain acceptable market share?
• Will our timing to market allow us enough competitive advantage to gain acceptable market share?

For an article devoted to strategic considerations for adding a delivery device to your drug product, click here.

[Updated 7/2/2025]

What complexities and/or additional responsibilities am I taking on by adding a device constituent to my drug or biologic?

Running a combination product program is definitely different from a drug-only program. Various stakeholders will have new needs and roles to fill, and there is a knowledge-curve that will require the acquisition of drug delivery device experts and/or training programs to ensure your internal team is ready for the task. Some areas that will be new or different are:

• Design: Drug design is focused on the disease, whereas device design is focused on the patient (user needs, human factors, user experience and useability) in addition to the safety and efficacy of drug delivery. Device design will also happen in partnership with an external device vendor, who will either provide an “off the shelf” device, a customized existing device, or a novel device.
• User: For a drug alone, physician training and education is required. For a self-administered combination product, patient training, education and increased post-market support are also needed.
• Regulatory: The regulatory filing and approval process becomes more complex when a device constituent is added to the mix. In addition to a BLA, you also have device/combination product regulations to which you must prove adherence.
• Manufacturing: New to the manufacturing process will be partnering with third-party vendors for fill and finish of your combination product.
• Payor: When your drug product becomes a combination product, most likely benefits switch from medical to pharmacy.
• Postmarket Activity: As mentioned above, a drug delivery device system requires the set up of an effective patient/user support program. Also required from a regulatory standpoint is a system for collecting and assessing both adverse events (as done for a drug alone) and patient complaints. Postmarket risk and change management based on market surveillance will also be a necessary function of your commercial team.
• Commercial Team Role: In addition to the above-mentioned postmarket activities that will be executed by your commercial team, the group will also have additional responsibilities in researching patient needs and market competition and informing device design to achieve a competitive product.

[Updated 7/15/2025]

What Device Strategy Supports the Drug AND the Business?

If you do pursue a device-enabled product, the question becomes not just what’s feasible, but what’s strategically aligned with your therapy and patient population. Unfortunately, this is where many startups feel overwhelmed. There’s often limited in-house expertise on device options, and the external landscape can be hard to navigate.

Here’s where executive oversight is critical. Too often, technical and clinical teams begin working with devices based on familiarity, speed, or availability—without clarity on whether the device actually meets the demands of your therapy, your users, or your brand. Rather than defaulting to what’s most familiar, like a prefilled syringe or a generic autoinjector, companies should start with user and product requirements, not the device itself.

Your oversight should guide teams to consider:

• Formulation constraints: Will the drug’s volume, viscosity, or stability limit device options?
• User requirements: Who is administering the drug – patients, caregivers, or clinicians – and what are their preferences and physical or cognitive limitations?
• Delivery setting: Will it be used in clinics, at home, or across both? Each scenario changes what success looks like.
• Dosing regimen: Daily, weekly, or as-needed dosing influences the usability and desirability of certain devices.
• Storage and handling: Does your product require refrigeration or reconstitution, and how does that impact device design?

For example, if your target population includes elderly patients with limited dexterity, a device that requires manual loading or multiple steps might undermine adherence. On the flip side, a fully integrated autoinjector with simple one-click activation could dramatically improve outcomes and reduce training needs.

It’s also critical to begin device partner conversations early. Device vendors can help you scope technical feasibility, timelines, and costs—but only if you’re clear on your goals. Don’t wait until Phase 3 to find out that your chosen device can’t accommodate your drug’s viscosity or stability requirements.

From a resourcing standpoint, this is also where companies should bring in external expertise early—not to outsource decision-making, but to prevent avoidable mistakes. An experienced team can help de-risk device assumptions before you lock in regulatory and supply chain commitments that are expensive to reverse.

Leaders should treat the device choice not as a technical decision, but as a core element of the product strategy made with cross-functional perspectives.

[Updated 8/7/2025]

Is connectivity (SaMD) a strategic advantage or a cost without a return?

Connected devices and digital companions (including Software as a Medical Device, or SaMD) continue to attract attention across the industry. They promise data visibility, better adherence tracking, and “smarter” patient engagement. But for  companies entering mid-phase clinical development, the key executive question is: does connectivity serve the business model? In practice, these promised features are only valuable if they are both clinically justified and commercially sustainable.

So how do you decide if your product needs to be “smart”?

Ask:

• Does the clinical model demand data feedback or remote monitoring? For example, do physicians need to know when and how often a patient has dosed?
• Will connectivity influence physician prescribing or payer acceptance? Does market research indicate that “smart” features will increase market share? Can the data be integrated into existing systems (like EHRs) or translate into better care or cost savings? If not, it may not justify the added development burden.
• Will connectivity improve outcomes? Can it actually prevent errors or enhance adherence in a measurable way?
• Can your organization support the software lifecycle? This includes cybersecurity, data storage, regulatory oversight, and software updates.

Connectivity should be a business enabler, not a novelty feature. The most common pitfall among early-stage companies is developing connected solutions without a plan to extract meaningful value from the data—whether for clinical feedback, payer negotiation, or patient support.

Executives should require any connectivity initiative to be tied to a measurable outcome (such as better adherence, faster approvals, reduced cost of care) or else deprioritize it until that case is clear. A smart approach to “smart” devices is to evaluate digital components as scalable postmarket enhancements, not defaults. Build the platform for connectivity only when it aligns with your clinical goals and commercial strategy.

On the other hand, a digital solution may aid in adherence and/or data collection within clinical studies even if not pursued commercially. This should be considered early to allow time for necessary development for clinical use when needed.

[Updated 8/21/2025]

Should I be launching with multiple Combination Products?

As companies prepare for commercial launch, there is often pressure to offer “choice” to the market, launching with a “portfolio” of delivery options—multiple device formats, dose configurations, or packaging models. The goal is flexibility, but the risk is fragmentation.

Each new variant:

• Requires its own design, validation, testing, and manufacturing workstreams
• Adds layers to regulatory pathways, scale-up logistics, and supply chain complexity
• Multiplies the burden on training, marketing, and support infrastructure

From the executive suite, it’s critical to define which use case will drive early value creation and prioritize around that. Your initial go-to-market strategy should be built on the device format that delivers the most impact to your highest-value users. Future variants can and should be planned, but only when the lead format is validated and stable.

Spreading too thin in the name of optionality can actually backfire. Launching lean is not a sign of conservatism. It’s a discipline that protects capital and speed. Our advice: Launch lean. Learn fast. Then scale intelligently.

There may very well be compelling market demand for multiple product presentations, but bringing the product to market quickly is almost always first priority.

[Updated 8/28/2025]

How Do We Know If Our Strategy Is Sound—and When Should We Intervene?

Every combination product strategy carries risk, and no team gets it perfectly right from day one. The question isn’t whether pivots will be necessary—it’s whether your organization is set up to recognize and respond to them early.

The best leaders aren’t the ones who prevent all challenges—they’re the ones who create systems that surface issues early and course-correct fast. When the market-facing, patient-facing, and technical perspectives are treated as peers at the decision table, better choices get made—and fewer surprises emerge late in the game.

Strong combination product strategies are built on iterative validation. That means:

• Getting patient feedback as early as possible (even before finalizing device specs)
• Running human factors studies that simulate real-world use
• Working closely with device partners to identify red flags
• Crafting a global product regulatory strategy and confirming that with regulators when necessary
• Keeping your internal teams aligned on strategy, scope, and risk

What’s often overlooked is how hard it is to make up for early missteps later. By Phase 3, many of your regulatory, IP, and device partner decisions are locked in. Phase 2 is the last best chance to refine or reset—and that window closes quickly.

Warning signs that warrant executive-level attention include:

• Inconsistent or delayed feedback from user testing
• Device development falling out of sync with drug timelines
• Regulatory uncertainty around device classification or software integration
• Internal misalignment between clinical, technical, and commercial priorities

Remember that it’s not a failure to pivot. It’s a sign of a mature team making informed decisions. In fact, it is common for companies to shift strategies in Phase 2 or even Phase 3 when it will result in a more viable product with better market fit. The danger lies not in realizing you need to change—but in being too slow or rigid to act on it.

Having flexible partnerships, a modular development plan, an open channel for regulatory engagement, and honest internal communication allows you to course correct without derailing your timeline.

[Updated 9/17/2025]

Questions about aligning stakeholders

Combination products—drug-device systems that integrate pharmaceuticals with delivery mechanisms—are increasingly critical to competitive success in modern pharma pipelines. For Phase 2-stage companies, building an integrated, cross-functional strategy early is essential. Alignment across internal stakeholders, vendors, and commercial teams lays the foundation for regulatory success, market readiness, and patient-centric design.

The complexity of combination products can’t be solved by layering device vendors onto a drug development program. Success requires a holistic rethinking of how your teams collaborate, how decisions are made, and where expertise is sourced.

Smart leaders will:

• Invest early in cross-functional education and integration.
• Build repeatable systems for stakeholder alignment.
• Treat the combination product as a unified, strategic asset—not a bolt-on.

You don’t get a second chance to build the right foundation. Phase 2 is your opportunity to do it right the first time.

This section explores best practices for aligning stakeholders during this pivotal phase of combination product development, organized around common, high-stakes questions.

How do I assess, select, and integrate vendor partners?

See our in-depth vendor selection and integration articles for comprehensive guidance.

Though covered in detail elsewhere, it’s important to emphasize here that vendor alignment is not just about sourcing technical expertise—it’s about operational synergy, shared risk, and timely execution. Device, testing, and manufacturing partners will influence everything from your risk profile to regulatory timelines. Cross-functional leaders should prioritize vendors that not only meet technical criteria but also demonstrate a willingness to align with your internal workflows and strategic objectives.

Key executive takeaway: Integrating the right vendors early reduces downstream friction, avoids rework, and supports regulatory and commercial readiness.

[Updated 10/3/2025]

What kind of training do each of my departments need to work together on my combination product?

The development of a combination product demands a shift in mindset across departments. Clinical, regulatory, quality, and commercial teams often work in silos, and introducing a device component into a traditionally drug-focused organization is highly likely to expose significant knowledge gaps.

Executive-level guidance:

• Regulatory and quality teams must be trained on Human Factors (HF), design control, and risk management under both drug and device regulations (e.g., ISO 13485, 21 CFR Part 820).
• Clinical teams need to understand how device design affects clinical trial design and endpoints, especially if a delivery method may influence safety or efficacy.
• Program managers must grasp the intricacies of device timelines and documentation, which are often unfamiliar compared to drug-only projects.
• Executive sponsors should ensure cross-training initiatives are funded and prioritized early—before Phase 3 program designs are locked.
• Commercial teams must be versed in the new considerations and activities that a drug-device delivery system entails. See two articles that dig deeper into this subject: Commercial Roles and Responsibilities / Commercial Considerations

Training doesn’t need to be overwhelming or academic. Brief, role-specific workshops can rapidly improve cross-functional fluency and enable more productive collaboration.

[Updated 10/9/2025]

How do we create systems for cross-departmental collaboration, communication, and inputs?

One of the biggest threats to combination product success is fragmented communication. Organizations often assume that simply inviting multiple departments to the table is enough—but in reality, lack of clarity around roles, ownership, and integration timelines causes costly delays and friction.

Best practices for executive leaders:

• Establish a combination product working group early—ideally by late Phase 2. This group should include leads from regulatory, quality, clinical, commercial, device engineering, and project management.
• Use a common planning framework (such as a systems map or integrated timeline) to identify and align all the dependencies between drug and device development milestones.
• Designate a “combination product lead”—not a PM, but a subject-matter-expert who can coordinate technical strategy, regulatory integration, and vendor oversight across teams.
• Standardize documentation expectations and meeting cadences, so teams can anticipate what is needed from them and when.

Most importantly, executives must model and reward cross-functional transparency. This includes acknowledging uncertainty, surfacing risks early, and engaging in structured decision-making.

[Updated 10/16/2025]

What does my commercial team need to know about combination products?

See our standalone articles for a deep dive into commercial considerations and commercial roles and responsibilities.

In short: commercial teams need to understand that combination products aren’t just about differentiating delivery—they are about defining the patient experience.

Key points for executive sponsors:

• Commercial must be engaged before the product design is locked. The voice of the customer—including patients, providers, and payers—should influence device form, usability, and support programs.
• Commercial leaders should understand how design decisions affect labeling, launch readiness, and reimbursement. For example, will your device require patient training? Can it be self-administered? Will it support value-based contracting?
• Equip the commercial team with the right combination product vocabulary so they can communicate internally with R&D and externally with stakeholders like the FDA (and other regulatory bodies), vendors, and other key opinion leaders without undermining credibility.

If your commercial team isn’t ready to own this kind of input, an early investment in training or external support can protect the integrity of the overall program.

[Updated 10/31/2025]

How do I need to talk to my marketing team about Combination Products?

Marketing teams often think in terms of brand, campaigns, and messaging—but combination products introduce a new layer of complexity that must be woven into early strategy development.

As an executive, your job is to:

• Help marketing understand that device characteristics are part of the product’s identity. It’s not just the molecule—it’s how, when, and where it’s delivered.
• Encourage early alignment between marketing and the HF/design teams. Marketing insights can shape critical usability and packaging decisions that impact adoption.
• Emphasize the long-term impact of device decisions. For example, will the device allow for lifecycle extensions? Could it enable differentiated indications or patient populations?

Many Phase 2 companies overlook this step because they see marketing as a post-approval function. But in combination product development, branding starts at the design table, not the launch pad.

[Updated 11/13/2025]

Being prepared to work with your OEM on drug-led combination products

By Phase 2, most sponsors discover that even “off-the-shelf” devices need program-specific definition—and that you, not the OEM, are the system owner. Treat the OEM as a critical partner that executes against your plan, not as the plan itself. The fastest programs make ownership expectations and processes visible early.

The bottom line: you (Pharma) are the system owner. Define the needs, own the design inputs and risk story, plan phase-appropriate OEM deliverables, integrate OEM outputs into a single, seamless record, and use the OEM as a partner to execute against your integrated plan. That’s how Phase-2 programs keep momentum through clinical builds and design transfer—without expensive or delaying resets.

What are the critical milestones in working with the Device OEM?

1) Pre-engagement (before selecting the OEM):

• Define user needs at the system level (drug + device + user + use environment).
• Translate user needs into high-level device selection criteria (dose, fill volume, viscosity, container closure, delivery rate, user interface, shelf-life assumptions).
• Use these to shortlist OEM platform options; device selection should follow user needs, not precede them. 

2) Vendor selection & joint kickoff:

• Contract for scope and capacityonly after you confirm you can meet the OEM’s “day-one” document asks (see below).
• Launch with ajoint integrated plan mapping your phase-appropriate design-control deliverables to OEM build gates (DV units, clinical/stability builds, design transfer). 

3) Design control execution (phase-appropriate):

• Design Inputs → Outputs → Verification → Validation → Design Transfer, with explicit deliverables and decision gates at each step.
• Your plan should showwhen OEM needs your inputs (e.g., to release tooling, procure long-lead parts, or schedule assembly/test slots) so you don’t “lose your place in line.” 

4) Build & test milestones:

• Engineering/DV buildsto confirm outputs meet inputs; clinical/stability builds to supply studies; design transfer into manufacturing with aligned control strategy. 

Progress should feel like a staircase: each gate requires named owners, dated deliverables, and go/no-go criteria. The most common slip is not technical but sponsors missing system documents the OEM needs to start or keep a build slot.

[Updated 11/20/25]

Who owns the Design History File (DHF)?

In any instance, the Pharma company should own it. The sponsor (Pharma) must maintain an integrated Design History File including OEM documentation as objective evidence and cannot rely solely on the OEM’s DHF or documents. Sponsors must own and maintain a master DHF, integrating relevant OEM documentation via supplier controls and technical agreements.

What information does the OEM provide to me?

Expect platform-appropriate design outputs (drawings, specs, BoMs, assembly/test methods) and, if in scope, data from OEM-executed testing that feeds your verification record. Manufacturing risk artifacts (e.g., PFMEA) and process capabilities inform your control strategy before release. You will also receive schedules and lead-time assumptions that depend on timely sponsor inputs. None of this replaces your design history; it complements it. Your job is to integrate OEM documentation into a coherent system record and make release decisions on that basis.

Scope varies by OEM and contract, but expect:

• Device design outputs and platform documentation appropriate to scope (drawings/specs, component lists, assembly methods).
• Inputs to your documentation (e.g., data that informs your risk files, verification plans/protocols) when the OEM performs testing per contract.
• Manufacturing risk artifacts such as PFMEA that must feed into your overall control strategy before release. Note: your overall control strategy should incorporate both design controls and manufacturing controls into a comprehensive strategy that ensures product quality and compliance across the entire lifecycle.
• Schedules/lead times and build slot requirements that depend on your timely inputs. 

[Updated 12/1/25]

What information / documents do I (Pharma) need to provide to the OEM? When?

Tie every handoff to a visible gate—tooling, materials, build start, protocol approval—so slippage is caught while it is still cheap.

Day-one / Kickoff

• User Needs (system-level)
• Preliminary Design Considerations (dose, fill volume, delivery rate, primary container/closure, interfaces, environmental/storage, usability drivers)
• Risk Management Plan and planning documents (who owns which risks, how decisions will be made)

During Design Input → Output

As design inputs mature with formulation data,

• Approved Design Inputs (requirements matured with formulation data)
• Use-risk drivers to inform device features/controls (feeds OEM design choices)
• Preliminary Verification Strategy (what you will verify, where OEM testing plugs in)

Verification / Validation phases

Entering verification/validation, finalize and share:

• Design Verification Master Plan and protocols (including OEM-executed testing where applicable)
• Acceptance criteria aligned to system risks and clinical needs
• Packaging/labeling/IFU expectations that affect builds and tests

Design Transfer

• Design Transfer Plan (who does what, when, and with what evidence)
• Control Strategy that integrates OEM PFMEA with your overall controls prior to release for commercial/clinical supply. Release for clinical or commercial supply only when those controls are credible.

[Updated 12/5/25]

What are best practices / keys to managing and collaborating with OEMs?

While there’s nuance to every partnership and project, below are eight critical best practices we apply to every Pharma-OEM relationship we support for clients.

1. Don’t assume “off-the-shelf” means turnkey. Platform devices still require program-specific tweaks you must define; budget and schedule for that definition work. 
2. Let user needs drive device selection. Pick the OEM after system needs are clear; reversing this order creates churn and lost slots. 
3. Make ownership explicit. Name a combination-product lead (SME) with authority to align technical strategy, regulatory integration, and vendor oversight—supported by PM, not replaced by it. 
4. Plan phase-appropriate deliverables. Map Inputs→Outputs→DV→VV→Transfer to real dates, owners, and OEM gates; treat the integrated plan as a contract. 
5. Integrate risk early. Start with a system-level risk plan and keep it live; use it to set verification priorities and acceptance criteria. 
6. Align control strategy before release. Combine OEM PFMEA with your control strategy before you approve release for clinical/commercial units. 
7. Protect capacity with readiness. OEM timelines assume you can deliver documents quickly; pre-build your core templates (user needs, inputs, RM plan, DVP) so you don’t “lose your place in line.” 
8. Right-size the contract. Scope what the OEM actually does (component only vs development + testing + finish-fill + packaging) so documentation expectations are realistic. 

[Updated 12/12/25]

Guidance for executives: Where to invest (first)?

It’s about phase-appropriate priorities and investments that affect change, eliminate avoidable rework, and move the ball forward.

• System-level ownership first. Focus on the combination product lead and core design-control templates early; this eliminates months of avoidable rework. 
• Risk-based verification. Put resources where acceptance criteria and verification protocols close your biggest uncertainties; de-scope “nice-to-have” tests that don’t change decisions. 
• Capacity insurance. Treat OEM capacity like a perishable asset: reserve it only after a document-readiness check; the most important investments you’ll make are those that prevent losing a build slot.
• Expert help. Used surgically, this often costs less than a missed build or a late discovery in verification, but the brief must be clear: make the sponsor’s system ownership stronger, not weaker.

More on selecting and managing your OEM

For more tips on setting yourself up for success with your device vendors, check out these two articles:

Are You Managing Your Combination Product Supplier Relationships Well Enough?

Nine Ways to Make Sure You Are Selecting the Right Device Constituent Supplier

[Updated 12/18/25]

What are the most common costly pitfalls in combination product development (and how can I avoid them)?

Combination product programs that pair a therapeutic with a device constituent hold immense promise for patients and investors alike. But for many pharmaceutical startups entering this space, the road is more complex than anticipated. The stakes are high: device considerations can influence regulatory outcomes, timelines, launch success, and even long-term market competitiveness.

From our experience supporting combination product teams, we’ve seen a set of common challenges that repeatedly derail programs. Each carries a heavy price tag, but each is also preventable with the right foresight. Here are four of the most common pitfalls, what they can cost, and the lessons learned from companies that have faced them.

1. Insufficient Quality Management in Place

The pitfall: Too often, pharma teams underestimate how rigorous a quality management system must be for a combination product. Device design history files (DHFs), risk management files (RMFs), and related documentation can’t be treated as an afterthought.

The cost: When regulators step in, the financial and reputational damage can be staggering:

• 483 observations ($100K–$250K in direct remediation costs, plus delays)
• Warning letters or import alerts ($50M–$500M+ in direct and indirect costs)
• Consent decrees reaching $2B in total costs

On top of direct remediation, there’s the hidden toll of lost sales from launch delays, plus distraction of team members from value-added activities.

The lesson: Building a strong quality system early isn’t just about compliance. It’s about protecting your launch window and your reputation in the eyes of regulators and investors.

2. Receiving a Complete Response Letter (CRL)

The pitfall: Device deficiencies or incomplete device information in regulatory submissions are a leading cause of CRLs. Many companies assume that a “drug-driven” submission strategy is enough, overlooking device requirements until it’s too late.

The cost:

• Direct remediation: ~$20M (testing, studies, staffing)
• Lost revenue: ~$500M from a 24-month delay (assuming $1B/year anticipated sales)

The lesson: Anticipating device-specific expectations from the start, especially in design controls and DHF content, avoids the devastating impact of a CRL. An upfront investment in integrated regulatory strategy can shave months or even years off of development timelines.

3. Discovering Too Late That the Device Platform Won’t Work

The pitfall: Selecting a device platform without fully aligning it to the program’s needs often backfires mid-development. Usability problems, clinical holds, or device partner limitations can force companies to switch platforms midstream.

The cost:

• 18 months lost transitioning and bridging to a new device
• ~$30M in additional backtracking expenses
• ~$375M in lost revenue from launch delays

The lesson: Device strategy isn’t just about “picking a platform.” It requires a thorough understanding of development, regulatory, and human factors from the start to avoid crippling delays later.

4. Launching with a Non-Competitive Product

The pitfall: Even if a program reaches approval, failing to anticipate patient, provider, or market needs can result in launching a product that simply doesn’t compete. Companies then find themselves scrambling to design a second-generation device.

The cost:

• ~$2–3M in additional Gen2 development expenses
• 30 months of delay
• ~$500M in lost market share opportunities

The lesson: Device strategy is central to commercial success. A thoughtful approach to device selection and differentiation at Gen1 can eliminate the need for a costly, reactive Gen2 scramble.

The Bigger Picture

What ties these scenarios together is a simple truth: investing early in device expertise saves enormous time and money later. For startups in particular, avoiding these pitfalls isn’t just about efficiency. It can be the difference between maintaining investor confidence and derailing a program altogether.

The most successful teams we’ve seen treat device considerations as integral to their combination product strategy, not as add-ons, yielding first-time-through success. With the right knowledge and foresight, the “bad situations” above become entirely avoidable, and your resources stay focused on bringing innovative therapies to patients faster.

[1/8/26]

Are there a template or best practices for developing an internal business case for a Combination Product development strategy?

When Pharma and Biotech leaders begin considering a delivery device for their therapeutic, one of the first challenges is not just deciding what device strategy makes sense—but justifying that decision to boards, investors, or other decision-makers who control funding. The natural question we hear from project leads considering a delivery device for the first time: is there a standard template or a set of best practices for building a convincing business case?

The short answer is that while no single template works for every company, there are best practices and common elements that strengthen a business case for combination product development. These can be tailored depending on whether your leadership team is already aligned on pursuing a delivery system, or if they still need to be convinced of its value.

If you would like guidance on how to create a successful internal business case for your combination product project, click here to read an actionable article and have the opportunity to gain access to example business cases.

Coauthored by:

Steven Badelt, Phd, Founder & CEO – Steve 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.

Carolyn Dorgan, Director, Technical Services – Carolyn Dorgan has 10+ years of experience in the Medical Device and Combination Product industries, including 6 years at the FDA leading the Infusion Devices team. Carolyn is active in the international regulatory community through speaking engagements and has participated in over a dozen international standards ranging from infusion devices, to needle-based injection systems, on-body delivery systems, and infant incubators.

Jonathan Amaya-Hodges, Consulting Director – 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.