7 Management Strategies For Combination Product Regulatory Success

By Fran DeGrazio, executive editor, Drug Delivery Leader

As I continue to work with industry, I am often reminded that some biopharma sponsor organizations remain challenged to meet current and evolving standards and regulations for combination products. This shortcoming may be due to lack of resources, lack of familiarity with the changing environment, or for many other reasons.

One key way to address the shortcoming and strengthen the organization’s preparedness is to bolster oversight at executive and management levels. A challenge for management when developing a combination product for market entry, especially if combination products are a new or recent venture for the organization, is identifying key factors necessary for successful outcomes. This challenge can become significant, even daunting, if executives and managers are not fluent in areas such as regulatory or quality. Gaps in fluency are particularly common when executives and managers come into their roles from non-technical backgrounds, a career trajectory that is also common.

To illustrate: One of the most consequential aspects in meeting today’s compliance standards is embedded in management’s responsibility to ensure that all activities necessary for providing a high-quality, low-risk product – one that is ultimately safe for patients – are properly completed. Executives and other managers must remember that the company holding the market authorization is responsible for the entire product. This includes associated vendor and service provider activities.

Without getting into the minutia, I will convey key points that executives and managers in the industry need to be aware of to adequately support their organizations. The coverage I offer here is certainly not all-encompassing but, rather, is intended to raise awareness and generate further interest. I especially have in mind non-technical leaders. For them, I aim to provide straightforward guidance on essential areas needed to successfully launch and support a combination product.

Below are seven recommendations for executives and other non-technical managers as they oversee combination product development:

#1: Lean On The Technical Experts

Executive management is not expected to know every regulatory, quality, or technical detail, but must hire subject matter experts for guidance in these areas. Management should support, not disregard, the expertise and advice of these professionals. Doing so can, at times, be a challenge, particularly when there are budget implications or time constraints.

A fundamental example of this support should be providing the necessary talent and time to build a thorough user input document. This critical activity often includes conducting interviews and working with clinicians and patients who will use the product being developed.

#2: Recognize That Combination Brings Complexity

Developing a combination product is more complex than, say, creating a drug in a vial, as it involves both drug efficacy and patient safety from both formulation and delivery device/system perspectives. Management must recognize the challenges of the significantly expanded cross-functional coordination required for successful commercialization of a combination product or combined use system. There are inherent complexities when combining areas from historically different disciplines such as biologics formulation development and device engineering.

Imagine, for instance, a formulation development scientist, who focuses on designing and optimizing the composition of a drug product to ensure its quality and stability (i.e., the chemistry), now engaging with an engineer working on the delivery device. These are quite different disciplines, as the engineer is most concerned about the function and delivery aspects (i.e., the functional/physical).

Not only are their disciplines different, but the regulations and the language they have historically worked within have been different.

#3: Amplify Voices Previously Less Relevant

Some disciplines that were less prominent in drug-focused work, such as materials compatibility and human factors, become increasingly important considerations during development and implementation of combination products. The budget should include resources allocated to enhancing these areas internally or to collaborating with external experts.

As an example, overt attention to Human Factors is now mandatory, emphasized by FDA guidance. Identifying critical tasks and creating use-related risk analysis (URRA) are required, as the FDA reviews these aspects closely to categorize tasks and to confirm that all risks are addressed through  Human Factors validation. If these aspects are not completed well, the review and approval process will slow.

#4: Acknowledge The Expansion Of Regulatory Demands

Regulatory frameworks for combination products now integrate both drug and device regulations. This expansion of applicable regulatory standards marks a departure from previous practices. Therefore, it  is essential for managers to be well-versed in current requirements to ensure compliance and maintain patient safety. Moreover, as with any drug product but even more so with combination products, not meeting current laws and expectations can mean significant loss of time and value with a program.

These two critical, foundational commitments must be in place:

• Robust Quality Management systems that address both drug and device requirements
• Sufficient resources to keep up with global regulations. Regulatory teams, as well as R&D, project engineers, management, and other functions, should understand these rules and their impact

#5: Prioritize Post-Market Surveillance

Managers with experience in drug development but less knowledgeable about device regulation should give considerable attention to a major area of concern: Post-Market Surveillance (PMS) and its associated requirements. Existing processes and systems for monitoring drug products post-market may not completely address the regulatory needs of commercialized combination products. These processes and systems must monitor both safety and performance once products have been released into the market and throughout their lifecycle.

Risks and adverse events should be examined, understood, and documented within specific time frames. This involves evaluating pharmacological properties, device malfunctions, and the chemical and physical compatibility of all individual components, as well as the complete, integrated system. Collecting and analyzing data from healthcare providers and users is essential. This process assists in identifying opportunities for ongoing improvement.

#6: Document, Document, Document

All completed design and development work must be risk-assessed and documented throughout the product lifecycle. Digital tools can enhance compliance and efficiency in this process. There are companies that specialize in providing software that is designed for cGMP environments and drug, device, and combination product activities. This reliance on purpose-built commercial software is the preferred way of addressing the documentation and knowledge management aspects, rather than using a self-developed database or spreadsheet. In-house attempts at building such tools typically result in gaps and insufficiencies, leaving the organization vulnerable to negative regulatory scrutiny.

#7: Counter Complacency, Monitor Regulations Regularly

In recent years, significant regulatory advancements have been achieved in the field of combination products. Regulatory reviewers and inspectors will proceed by aligning their expectations with the updated requirements as well as with recognized best practices they have observed in other biopharma sponsor organizations.

For those reasons, it is important for executive management to avoid complacency — in themselves and in the organizations they lead — regarding these evolving regulations. Organizations, especially executive and managerial leaders, should actively familiarize themselves with tailored rules, new guidances, and best practices, supporting the implementation of them as appropriate. Engaging subject matter experts and professional consultants can provide valuable insight when needed, especially around the myriad technical matters that are likely to emerge in combination product development.

Remember, combination products hold considerable strategic importance for pharmaceutical and biopharmaceutical companies. When appropriately developed with a patient-centric approach, these products can optimize commercial opportunities within the healthcare sector. However, realizing these benefits requires strict adherence to current regulatory standards.