Combination Product Industry News & Guidance

You are the Commercial Team for a Pharma company that has just decided to introduce a Combination Product…

What do you need to know?

Excellent question, because your job is about to change and a whole new slew of considerations and activities are heading your way.

Let’s start with making sure you understand what it is you are dealing with. We are talking about Combination Products, specifically drug delivery device systems. A Combination Product is a product comprised of two or more regulated components physically, chemically, or otherwise combined or mixed and produced [21 CFR 3.2(e)]. Each individual product in this combination is a constituent part. For a drug delivery device system, there is a drug or biologic constituent part and a device constituent part. The drug/biologic component refers to any ingredient intended for use in the manufacturing of a drug product, including those that may not appear in the drug product [21 CFR 210.3(b)(3)]. The device component refers to any raw material, substance, piece, part, software, firmware, labeling, or assembly which is intended to be included as part of the finished, packaged, and labeled device [21 CFR 820.3(c)].

Combination Products can be cross-labeled (constituent parts sold separately but specifically labeled for use together), co-packaged (constituent parts packaged and sold together), or single-entity (chemically or physically combined constituent parts).

Separate Products With Cross-Labeling

• Light-activated drugs/biological products labeled for use with a specific light source device

Co-Packaged Products

• Empty syringes packaged with a drug product
• Empty injection systems packaged with a drug product
• Transfer sets
• Lyophilized drug product vials packaged with reconstitution components.
• Surgical kits containing both a drug and a device to be used with it

 Single-Entity Products

• Prefilled syringes
• Prefilled auto-injectors
• Metered-dose inhalers
• On-Body Delivery Systems
• Dry powder inhalers
• Nasal spray
• Transdermal patch systems
• Prefilled iontophoresis system Microneedle “patch”
• Drug pills embedded with sensors
• Contact lens coated with a drug
• Drug-eluting stents
• Drug-eluting leads
• Condoms with spermicide
• Dental floss with fluoride
• Antimicrobial coated catheters/sutures
• Bone cements with antibiotics
• Live cells seeded on/in a device scaffold
• Extracorporeal column with column-bound protein

How does introducing a Combination Product Change the Game?

The reason your company is heading down this road is for competitive advantage. It allows for a potentially less time-consuming, less stressful, less costly at-home experience for the patient. When a drug delivery device makes sense for a particular drug, patient group, and market, it can mean putting your brand and life-changing health solutions directly in the hands of patients. When you can get to that market first and/or offer a novel and positive experience to the end user, you can find competitive advantage.

The interaction between a patient and a device is often more intimate and involved than with just the drug. While the medication often plays a pivotal role in enhancing the patient’s health condition, it’s the device, along with its packaging and labeling, that the patient directly engages with and associates with your brand. The patient may not be interested in or aware of the intricate technicalities, but they desire a product that integrates their treatment effortlessly into their daily routine. It is this human interaction with the therapeutic functions that is the reason for the Combination Product regulations that began to emerge in 2012. The Pharma industry is relatively immature in terms of medical devices. This usually means that device teams and their commercial counterparts are all working within an organization that “doesn’t get it.” The rest of the team bringing your drug delivery device system to market are not used to focusing on the human interaction with their product and they are not familiar with the regulatory, quality, vendor management, and commercial activities that must be aligned for launch success. The constraints caused by lack of understanding and cross-functional alignment can affect your ability to provide the optimum patient experience.

The first new understanding that needs to be shared across the organization is that Combination Products bring a more complex regulatory process.

Pharma must move from the perception that you can just put a drug in a syringe and ship it “like always” and instead integrate a device process that requires additional steps (and prevents you from making changes without additional testing and documentation). Drug development begins long before it is even possible to begin making decisions on device selection and development. Timelines for when to begin and pathways for development and regulatory success are not always the same. It is generally accepted that to begin a device development program you need some baseline inputs. For example, the intended dose volume, target injection time (TPP) – in the case of an AI/OBI, formulation information such as viscosity and essential clinical information related to  administration routes or potential intended users. But, the sooner you begin thinking about your device, the better. Decisions the drug team makes in Phase 1 and Phase 2 clinical studies can have downstream effects on what devices can be considered. Patient, commercial and marketing/business needs can also have upstream effects on device design and, therefore, drug development decisions. That said, there are pathways to be forged when you start Phase 2 with a device and others that include bridging studies when you begin with one device then switch to another.

It is important to understand what impacts Combination Product development timelines.

Identifying the downstream and upstream implications of certain development decisions made by various functional partners in the development process is critical to keeping your project on time and on budget. Below is a list of some common example decisions that can affect your development timeline and influence the types of design choices and devices available to you.

Formulation Choices

• Early decision on the formulation, concentration, viscosity, and volume

Intended Users and Use Environments

• The intended use environment of your drug delivery device (Home use vs. Clinical)
• Potential age ranges of intended users and prior experience with similar drug delivery devices
• Comorbidities that may influence design choices such as dexterity or cognitive constraints

As you move through your development, these early choices will begin to constrain your design space. As the design evolves, the team will need to continue to make timely and critical decisions to translate from the Clinical, Commercial and User Needs into the engineering requirements.

Design Choices

• The complexity of the drug delivery device and its use often define the scope of the engineering requirements
• These requirements in turn increase the scope of applicable standards, guidance and testing including real time aging
• The drug delivery device not only requires benchtop engineering testing but often formative and summative Human Factors evaluations to inform design decisions and validate the user needs have been met when representative devices are provided to intended users.

CMO and CDMO Partnerships

• Complexity of the device will drive the constraints on the manufacturing including assembly and filling
• Projected commercial volumes will influence manufacturing strategy, scale and complexity
• CMO experience with similar technologies should be accounted for when selecting CMOs for final assembly and scale up

Design Changes

• Poor planning early can increase the chances of design issues and changes later into the development
• Changes later in the process increase the number of tests, which mean an increase in time and money

Let’s say, for example, that you have completed the design of a product and it is past the stage of design freeze. It has gone through the internal governance process and certain design components have been submitted, including size, color and volume fill. As the Commercial Team continued to do market research, they concluded that a change in color is warranted on the outside packaging (box) and on the device. What is the impact of this change? You are looking at:

• Design change managed via a formal Change Control process
• Re-execution of a subset of testing, for example biocompatibility or certain functional testing
• Potential label changes to instructions for use or other training materials that could constitute new Human Factors validations.
• Timeline delays and the need for a newly proposed commercialization date
• Additional costs to the development budget
• Potential human resourcing issues

Aligning the right departments and decision makers in this more complex team structure is critical to success.

In the aforementioned scenario, pinpointing the correct decision-makers is crucial. These could be a single person or a multidisciplinary team, and they should be at the suitable leadership tier. The individuals who might need to contribute to the decision-making process or make the ultimate choices could come from any of the partners listed below, all of whom play a role in the creation and introduction of a drug delivery device system.

Device Side

• Development/Engineering
• Device Quality
• Device Regulatory
• Human Factors
• Device Partner(s)

Drug Side

• Drug Product Formulation
• Supply Chain
• Manufacturing
• Quality Control
• Regulatory CMC
• Program Management

Other Functional Areas

• Clinical Development
• Commercial/Marketing
• Medical Affairs
• Regulatory (Clinical)
• Business Development
• Drug Safety/Pharmacovigilance

How does the Commercial Team fit into the Combination Product equation?

While the product doesn’t land in the Commercial Team’s lap until after Clinical Stage activities are being completed, the Commercial Team has an important role of providing inputs that should begin in the early portfolio management and strategic planning stage.

Commercial Team activity starts at the beginning of the project, during strategic planning.

Market and competitive research will inform whether to pursue a particular drug delivery device system in the first place, as well as basic requirements based on user needs and wants and the metrics for what success will look like within the overall program goals. Critical inputs continue through device design / development and launch / post-market preparation begins well before the new drug delivery device system is approved and ready for market.

Below is a table of Commercial Team role and responsibility examples to paint the larger picture.

The Commercial Team’s inputs have an impact on patient adherence.

Responsibilities that fall under the domain of the Commercial Team can have a direct effect on patient experience and, therefore, patient adherence (and therefore the long-term market success of your product). There are many factors that contribute to a patient’s adoption and adherence to a treatment, including socio-economic factors, the constraints of the health care system, the condition, the therapy, and the patient themself.

For example, 64% of Americans avoid or delay treatment due to cost.¹ Knowing the socio-economic situation of the end users in your product’s market(s), the Commercial Team can provide inputs on price points that won’t price the product right out of patient hands, and also set cost-friendly reimbursement, promotional, distribution, and post market strategies. 

In medical device use studies, more than half of 700 patients surveyed who self-inject admitted they did not completely understand the instructions for use (IFU) prior to beginning treatment² and 84% of patients failed to demonstrate correct use of an autoinjector³. Sharing data and design inputs for the combination product’s IFU is an important role of the Commercial Team and one that can directly impact the effectiveness of this user tool. Creating and executing various training and support tools for patients and end-users, such as training devices, documents, videos, and phone scripts can reduce user anxiety and use error and increase patient adherence and safety. Setting up a patient support hub with both digital resources and human-interactive support can do the same, resulting in a positive user experience and continued adherence and loyalty to your product.

Where do Commercial Teams usually go wrong with Combination Products?

 No one does everything right the first time without a little expert birdie whispering in their ear. That’s where Suttons Creek comes in. We have worked on the full landscape of drug delivery devices out on the market, plus some novel ones currently being innovated. We have seasoned team members who began this work when the combination product regulations first emerged, and have hands-on experience with the newest guidelines and practices that get a combination product approved and competitively out in the market. We have seen where your industry counterparts have gotten it right…and wrong. Our job for our clients – and in this article – is to share our knowledge both about best practices and how to avoid common missteps. We have highlighted a few below.

Strategic Planning

• Insufficient voice of the customer (VOC) market research when identifying and establishing patient-centric requirements
• Assuming what worked in the past is the best commercialization approach for the current product/market
• Ignoring regional markets and taking a global approach
• Believing technical features and clinical efficiency alone are going to sell the product
• Not conducting a limited, controlled launch of a new/modified device

Resourcing

• Not expending adequate resources to identify and create customer solution and market awareness
• Under-resourcing digital marketing vs. general marketing creation activities

Training

• Not understanding company QMS, device complaint reporting procedure, complaint outcome and User feedback process
• Insufficient User training activities: HCP, Staff, Patient, Pharmacy

Post Market

• Inadequate feedback process from the field directly to senior management (i.e., field issues, competitive intelligence, new products, market trends)

Where do you go from here?

As we have mentioned, it is important to grasp all of the complexities and new considerations of the combination product world. Continue your education through targeted reading and trainings that can help you understand your new role and responsibilities. You can also arrange for cross-functional internal trainings, so the divisions that need to collaborate better understand each other’s drivers, key timings, necessary inputs and project goals.

It is also critical to align departments/partners (both internal and outsourced, such as CMOs and OEMs). Ensure the proper channels of communication are put in place, goals and processes are aligned, and decision-makers are identified. We outlined a large team that needs to come together above in this article. As the Commercial arm of this team, your best bet to get alignment initiated is to reach out to your Program Manager and your Regulatory Manager.

And if you find you need a little expert birdie to whisper in your ear, that is always a good path to pursue in this innovative, ever-evolving combination product game.

Authored By:

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

1. https://www.carepayment.com/new-carepayment-research-shows-americans-cant-afford-medical-bills/
2. Pharmaceutical Research and Manufacturers of America (2013). 2013 Overview medicines in development.    Retrieved from http://phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf
3. ] Bonds, R., Asawa, Al, & Ghazi, A. (2014, November 18). Misuse of medical devices:  a persistent problem in self-management of asthma and allergic disease.  Retrieved from www/annallergy.org/article/s1081-1206(14)00752-2/fulltext