Post Market Strategies/Lifecycle Management of Co packaged Drug/Device Combinations – A Device Manufacturer’s Perspective

Post-market surveillance reporting and lifecycle management of drug products are vital to the safety of patients, as these activities allow for long-term monitoring of drug effects. When a device is co-packaged with a drug, the device manufacturer must also follow thorough post-marketing activities and maintain a systematic lifecycle management process to ensure the device is safe and effective as both a stand-alone device and co-packaged product throughout the life of the device.

This discussion will focus on the device and key post-market strategies and lifecycle management responsibilities of the device manufacturer, specifically when the device is co-packaged as a drug/device combination in the United States and European Union. The partnership between the device manufacturer and drug manufacturer is critical for combination products to facilitate the exchange of post market data and requirements throughout the lifecycle.

What is a Co-packaged Combination?

According to the United States Food and Drug Administration's (US FDA) definition under US FDA 21 CFR 3.2 (e)(2), a co-packaged combination consists of "two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products."

This definition is divided into three distinct categories, which include:

• Single-entity - products are chemically or physically combined (e.g., prefilled syringe, filled IV bag, inhaler)
• Co-packaged - products are packaged together (e.g., convenience kits such as a first-aid or surgical kit, drug or vaccine packaged with a syringe)
• Cross-labeled - certain separately distributed products for combined use, clearly related through labeling (e.g., photosensitizing drug and activating light source or laser)

For more information, refer to https://www.fda.gov/combination-products/about-combination-products/combination-product-definition-combination-product-types.

Similarly, the European Union (EU) has its own set of explicit definitions, broken down into two main categories:

• Integral - products are chemically or physically combined to form one single integrated product
• Co-packaged - products are packaged together in the same secondary packaging

For more information, refer to: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-documentation-medicinal-products-when-used-medical-device-first-version_en.pdf

Medical Device Lifecycle Management:

With regards to lifecycle management, it is important to remember there are steps before device conception and that the lifecycle does not simply end with post-marketing. It is a constant feedback loop back into the full lifecycle management approach.

To begin, there should be a marketing plan to define the market needs, while simultaneously working on the design concept and strategy for the product. Typically, this process may go back and forth many times before moving into the device development phase. In development, there will be verification and validation testing to ensure the device meets all product requirements and is determined to be safe and effective for its intended purpose. From there, the first regulatory submission will be initiated and approved. Once approved in the given market(s), the post market lifecycle management process can begin.

After product launch, device manufacturers may learn about market changes, production and post-production evaluations, quality auditing, post-market surveillance, and other feedback that could impact the device. This "feedback loop" can bring the device back into the development phase. Meaning, there may be a need for design, process, and/or manufacturing changes to continuously ensure the device is safe and effective for its intended purpose.

Hence creating for a robust lifecycle management process.

Post-Market Throughout Lifecycle, Including Change Management:

Post-Market Surveillance

Post Market Surveillance (PMS) and monitoring are required by regulations and regulatory bodies (like the FDA and EU MDR), but more importantly, it is a means for manufacturers to ensure their device(s) continue to perform safely and effectively for their intended use, in the intended use environment.

With strong post market activities, device manufacturers can monitor the device safety and clinical efficacy, look for device design improvements, and potentially find manufacturing quality improvements. Without a robust post market system, safety issues like device malfunctions could be missed or even issues that could lead to serious health consequences, like a patient's death.

Postproduction or post market has its own needs. It is important to understand how post market impacts other specific areas of the product lifecycle, specifically risk management and clinical evaluation. For instance, complaint information can be utilized to better evaluate risks. The identified risks can aid in determining the benefit-risk ratio for the given device. Then, the state of the art can be determined through various post market activities in conjunction with the benefit-risk profile and clinical benefit. In these examples, the connections are clear connections between post market, risk, and clinical evaluation.

Sources of Post-Market Data

Proactive and reactive PMS activities from internal and external sources are both equally important for a robust PMS System.

Some examples of proactive data:

• Surveys
• Focus Groups
• Product registries
• PMCF Studies
• Clinical trials (e.g. National Institutes of Health ClinicalTrials.gov)
• Social Media
• Competitor and similar device data

Reactive PMS is a passive form of data collection as this information typically comes from an event that has already occurred. Reactive data can include:

• Internal & external data sources (e.g. nonconformances, corrective actions)
• Complaints, including adverse events
• Maintenance and installation records
• Customer returnsClinical and scientific literature (e.g. NIH PubMed)
• Risk Data
• Regulatory authority warnings and safety alerts
• Publicly accessible databases on adverse events and advisory notices (e.g. MAUDE, EUDAMED, MedSun)

Change Management

As device manufacturers learn about our device through the PMS process, specifically complaint and trending results, changes may appear that impact the device design or manufacturing process.

The change management process must be robust, and a continuous effort between the device and drug manufacturer to ensure continuous improvement of the product.Global regulations require thorough and systematic change management activities starting in the design phases and then throughout the full life cycle of the product including into post market surveillance.

It is important that changes are fully assessed for risks, including a full regulatory impact assessment, as a breakdown in the change management process could result in product recalls, adverse events, malfunctions and more.

Complaint Trending and Reporting

Complaints are defined as "any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution" by US FDA 21 CFR 820(b).

Monitoring of complaints for trending is required to be conducted by device manufacturers.

Trending can be defined as any statistically significant increase in the frequency or severity of not serious incidents or undesirable side effects which could have a significant impact on the benefit-risk analysis and could be risks to the health or safety of patients, users or other persons that are unacceptable when weighed against the intended benefits.

Trend reporting can be completed daily, weekly, monthly, etc., it's the device manufacturer's responsibility to determine the frequency. The frequency is based on risk, which is based on negative trends or safety issues identified. The frequency is intended to be established in comparison to the foreseeable frequency or severity of such incidents.

While there is no fixed number or limits defined by regulators for when something is to be reported, if the number of complaints exceeds the limit defined by the device manufacturer as unacceptable, then an investigation should be conducted to analyse what exactly is happening and if action needs to be taken.

Device and Drug Manufacturer Partnership throughout the Product Lifecycle:

Classification and Submission Pathways

Before starting a regulatory submission for a co-packaged combination, the product must be adequately classified in the given market, and the drug and device manufacturers must have clarity on any technical challenges and regulatory requirements in the intended market early on.

Here is an example involving an On-Body Delivery System (OBDS) + Drug Product:

In the EU, according to Regulation (EU) 2017/745 (MDR), Annex VIII, Chapter 3, Rule 12, "All active devices intended to administer and/or remove medicinal products, body liquids or other substances to or from the body are classified as class IIa, unless this is done in a manner that is potentially hazardous, taking account of the nature of the substances involved, of the part of the body concerned and of the mode of application in which case they are classified as class IIb."

Meaning, if the drug packaged with the OBDS is for life support, it shall be a Class IIb, but if this drug is for normal drug use, it is a lower risk and therefore classified as a Class IIa.So for an OBDS device, the device manufacturer needs to obtain a CE marking in the EU. However, depending on what drug manufacturer the device manufacturer is partnered with, the classification of the device may change. Therefore, the requirements needed in the technical documentation and auditing requirements may be different. Therefore, it is imperative that this information is discussed early in the submission process or ideally in the design development stages.

Quality Agreements

Quality agreements between manufacturers of each constituent part of the co-packaged combination product help ensure compliance, transparency, and communication for the overall product by defining each party's roles and responsibilities, detailing frequency of required communications, providing responsibilities surrounding internal and external audits, and more. Specific to post-market, the agreement is also intended to cover the shared responsibilities for complaint handling, trending, reportable events, change management, and country specific requirements.A quality agreement between the device and drug manufacturer is not only helpful, but it is also a requirement in many territories to have in place.

Post-marketing and Complaints Process

While the device manufacturer follows its own complaint process on the device itself, it is also a joint effort with the drug/biologic manufacturer when a drug is involved. The quality agreement between the drug manufacturer and Medical Device Registration Holders serves as a formalized mechanism to keep both parties informed. The agreement also ensures complaints are investigated and events are reported in adherence with applicable regulations.

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