Elena Mack and Kevin Lentz, Vice President, Quality Innovation and Systems, West and Senior Director Regulatory Affairs, West 11.07.17
The relationship between pharmaceutical manufacturers and drug delivery technology providers has evolved as combination products occupy a more substantial market segment. Instead of operating as separate entities developing individual products, the two parties are collaborating early and often to ensure self-administered therapies are safe, easy to use and effective.
While patient-facing features of combination products are most important, collaborative efforts that address potential regulatory challenges are also critical. Throughout the development, testing and marketing phases of combination products, direct attention must be given to ensure the drug and delivery platform meet compliance standards individually and once they are combined.
The need for early collaboration is especially important when a combination product is to be marketed in multiple countries. The move to a “single team” approach can pave a smoother path through the regulatory submission and approval processes, reduce the amount of time it takes to get combinations products to market and better position both parties for product updates and future products across the globe.
Example of regulatory variances
The first step to regulatory approval points out how strategies vary, depending on where a product is being marketed. For example, the FDA defines a combination product as “a product comprised of any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product.”
The EU does not make such a distinction, because combination products are regulated as either a drug or device. The comparison explains the very different steps required before submission is even entered, which underscores how important it is for drug and technology partners to work closely together.
United States
In the U.S., the FDA has regulatory guidelines designated specifically for combination products, but there are three potential submission pathways within that designation:
“The single mode of action of a combination product that provides the most important therapeutic action of the product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.”
Or more simply, which part of the combination product is most crucial to delivering the results necessary to effectively treat a condition? The FDA recognizes device, drug or biologic as the three possible PMOAs for a combination product, and the regulatory agency that it will be submitted to is based solely on the PMOA determination:
European Union
While there are similarities for regulatory guidelines and submission in the EU, there are some very important differences. Unlike the FDA, which has a specific designation for combination products, the EU requires the product to be submitted as either a drug or a device to earn a CE mark.
Determining whether a combination product should be submitted as a drug or device will impact how it’s regulated upon approval, as drugs and devices are subject to different regulations. PMOA is the deciding factor that guides which pathway is appropriate.
For example, single-use therapies that can be delivered in variations of the device, such as pre-filled insulin syringes, are classified as a drug. When the drug’s effectiveness requires a specific delivery platform, it is considered a device.
This example alone supports the assertion that collaborative efforts between pharmaceutical manufacturers and drug delivery technology providers is a non-negotiable aspect of marketing combination products across multiple countries.
Building a collaborative infrastructure
It is wise for collaboration to begin years before the initial interface. This allows pharmaceutical companies and drug delivery technology providers time to develop an end-to-end timeline, which should take the drug and device development stages into account. The best collaborative efforts have no definite end date. Should problems arise, having a history of working together will create the opportunity for easier mitigation.
Having one team with representatives from both companies leads to more innovative revisions and, in some cases, create a faster path to market for new combination products. Without that collaboration, combination products will be less successful and the companies will be less prepared to quickly address the challenges that will inevitably occur. Transparency is also important, both parties should be able to have difficult discussions to ensure issues are resolved sooner rather than later. Resolving problems early on makes the collaboration more profitable as the relationship grows.
The infrastructure of the collaboration should be supported by four key pillars: strategic alignment, proactive regulatory awareness, lifecycle support and continuous improvement.
Strategic alignment
Pharmaceutical manufacturers and drug delivery technology providers must be keenly aware of each other’s business and technical imperatives across regions as these imperatives may vary in the multiple countries in which they operate. For example, consider the level of information required at an early clinical phase. Such data may not be the same from one geography to another. Regulatory support functions should be adaptable and specific to the needs of each party relative to where the product will be marketed.
Understanding the potential challenges each party will face can eliminate potential delays in approval. In addition, a productive rapport should be maintained with regulatory agencies around the world. For many combination products, it may be necessary to have experts who understand current regulations in all potential countries where the combination product may be available.
Maintaining awareness and engaging in productive dialogue can provide regulatory departments with the knowledge to further enhance the quality of its regulatory information. Once again, this translates into more effective support for regulatory submissions.
Proactive regulatory awareness
In addition to having expertise related to current regulations, it is just as important to look ahead to potential changes and emerging trends. Regulatory affairs departments should monitor global regulatory trends and share their findings with one another to address potential regulatory changes that could affect approval. Even after a combination product has been introduced, it remains important for all parties to remain diligent in keeping up with regulatory trends, as such changes could impact plans for product revisions – and in some cases, force a revision sooner rather than later.
By combining each party’s expertise and strategic planning, regulatory departments from the pharmaceutical manufacturer and drug delivery technology provider can assist one another to provide proactive support as changes to regulations are being considered and eventually enacted.
Lifecycle support
To ensure an optimal product, pharmaceutical manufacturers and drug delivery technology providers must provide strategic support throughout all stages of a combination product’s life cycle, including drug discovery, development and all phases of clinical studies, as well as commercial and post-commercial activities.
Comprehensive regulatory expertise and submission support should span all of these phases of a pharmaceutical manufacturer’s drug product lifecycle in every country the combination product will be available. This approach becomes especially important as the manufacturer progresses from clinical development into marketing approval and beyond to post-approval maintenance of their applications and licenses.
Continuous improvement
Combination product teams must continue to evolve to meet the changing regulatory landscape. In addition to implementing strategic alignment, proactively keeping tabs on regulatory trends and changes and instituting lifecycle support, both parties must monitor their own processes and manufacturer outcomes and share data with the greater team in every country where the product will be available.
That information should be used to articulate areas where improvements can be made to reduce potential regulatory impediments and foster an environment where continuous improvement is encouraged and expected.
Sources for continuous improvement include:
geography.
Conclusion
When marketing a combination product globally, the importance of a collaborative relationship between pharmaceutical manufacturers and drug delivery technology providers cannot be overstated. To successfully work together, the two parties must have a collaborative infrastructure that is based on strategic alignment, proactive regulatory awareness, lifecycle support and continuous improvement globally, allowing the team to:
Elena Mack possesses over 19 years experience in quality assurance and regulatory affairs. She has an extensive background in microbiology, manufacturing operations and regulatory affairs in biopharmaceutical, medical device (PMA/510K), liquids/semi-solids (Rx & OTC), contract manufacturing, cosmetic and aseptic processing environments. Elena holds three ASQ certifications—CQA, CMQOE and CPGP—a BSc in Microbiology from University of the Sciences in Philadelphia and a MSc in Quality Assurance & Regulatory Affairs from Temple University.
Kevin Lentz possesses over 20 years’ experience in regulatory affairs and quality assurance. He has an extensive background in medical device (wearable, implanted, delivery systems), tissue products and combination products regulatory affairs. Kevin holds a BSc in Physical Chemistry from York College of PA.
While patient-facing features of combination products are most important, collaborative efforts that address potential regulatory challenges are also critical. Throughout the development, testing and marketing phases of combination products, direct attention must be given to ensure the drug and delivery platform meet compliance standards individually and once they are combined.
The need for early collaboration is especially important when a combination product is to be marketed in multiple countries. The move to a “single team” approach can pave a smoother path through the regulatory submission and approval processes, reduce the amount of time it takes to get combinations products to market and better position both parties for product updates and future products across the globe.
Example of regulatory variances
The first step to regulatory approval points out how strategies vary, depending on where a product is being marketed. For example, the FDA defines a combination product as “a product comprised of any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product.”
The EU does not make such a distinction, because combination products are regulated as either a drug or device. The comparison explains the very different steps required before submission is even entered, which underscores how important it is for drug and technology partners to work closely together.
United States
In the U.S., the FDA has regulatory guidelines designated specifically for combination products, but there are three potential submission pathways within that designation:
- Center for Devices and Radiological Health (CDRH)
- Center for Drug Evaluation and Research (CDER)
- Center for Biologics Evaluation and Research (CBER)
“The single mode of action of a combination product that provides the most important therapeutic action of the product. The most important therapeutic action is the mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product.”
Or more simply, which part of the combination product is most crucial to delivering the results necessary to effectively treat a condition? The FDA recognizes device, drug or biologic as the three possible PMOAs for a combination product, and the regulatory agency that it will be submitted to is based solely on the PMOA determination:
- Devices – CDRH
- Drugs – CDER
- Biologic – CBER
European Union
While there are similarities for regulatory guidelines and submission in the EU, there are some very important differences. Unlike the FDA, which has a specific designation for combination products, the EU requires the product to be submitted as either a drug or a device to earn a CE mark.
Determining whether a combination product should be submitted as a drug or device will impact how it’s regulated upon approval, as drugs and devices are subject to different regulations. PMOA is the deciding factor that guides which pathway is appropriate.
For example, single-use therapies that can be delivered in variations of the device, such as pre-filled insulin syringes, are classified as a drug. When the drug’s effectiveness requires a specific delivery platform, it is considered a device.
This example alone supports the assertion that collaborative efforts between pharmaceutical manufacturers and drug delivery technology providers is a non-negotiable aspect of marketing combination products across multiple countries.
Building a collaborative infrastructure
It is wise for collaboration to begin years before the initial interface. This allows pharmaceutical companies and drug delivery technology providers time to develop an end-to-end timeline, which should take the drug and device development stages into account. The best collaborative efforts have no definite end date. Should problems arise, having a history of working together will create the opportunity for easier mitigation.
Having one team with representatives from both companies leads to more innovative revisions and, in some cases, create a faster path to market for new combination products. Without that collaboration, combination products will be less successful and the companies will be less prepared to quickly address the challenges that will inevitably occur. Transparency is also important, both parties should be able to have difficult discussions to ensure issues are resolved sooner rather than later. Resolving problems early on makes the collaboration more profitable as the relationship grows.
The infrastructure of the collaboration should be supported by four key pillars: strategic alignment, proactive regulatory awareness, lifecycle support and continuous improvement.
Strategic alignment
Pharmaceutical manufacturers and drug delivery technology providers must be keenly aware of each other’s business and technical imperatives across regions as these imperatives may vary in the multiple countries in which they operate. For example, consider the level of information required at an early clinical phase. Such data may not be the same from one geography to another. Regulatory support functions should be adaptable and specific to the needs of each party relative to where the product will be marketed.
Understanding the potential challenges each party will face can eliminate potential delays in approval. In addition, a productive rapport should be maintained with regulatory agencies around the world. For many combination products, it may be necessary to have experts who understand current regulations in all potential countries where the combination product may be available.
Maintaining awareness and engaging in productive dialogue can provide regulatory departments with the knowledge to further enhance the quality of its regulatory information. Once again, this translates into more effective support for regulatory submissions.
Proactive regulatory awareness
In addition to having expertise related to current regulations, it is just as important to look ahead to potential changes and emerging trends. Regulatory affairs departments should monitor global regulatory trends and share their findings with one another to address potential regulatory changes that could affect approval. Even after a combination product has been introduced, it remains important for all parties to remain diligent in keeping up with regulatory trends, as such changes could impact plans for product revisions – and in some cases, force a revision sooner rather than later.
By combining each party’s expertise and strategic planning, regulatory departments from the pharmaceutical manufacturer and drug delivery technology provider can assist one another to provide proactive support as changes to regulations are being considered and eventually enacted.
Lifecycle support
To ensure an optimal product, pharmaceutical manufacturers and drug delivery technology providers must provide strategic support throughout all stages of a combination product’s life cycle, including drug discovery, development and all phases of clinical studies, as well as commercial and post-commercial activities.
Comprehensive regulatory expertise and submission support should span all of these phases of a pharmaceutical manufacturer’s drug product lifecycle in every country the combination product will be available. This approach becomes especially important as the manufacturer progresses from clinical development into marketing approval and beyond to post-approval maintenance of their applications and licenses.
Continuous improvement
Combination product teams must continue to evolve to meet the changing regulatory landscape. In addition to implementing strategic alignment, proactively keeping tabs on regulatory trends and changes and instituting lifecycle support, both parties must monitor their own processes and manufacturer outcomes and share data with the greater team in every country where the product will be available.
That information should be used to articulate areas where improvements can be made to reduce potential regulatory impediments and foster an environment where continuous improvement is encouraged and expected.
Sources for continuous improvement include:
- Regulations, guidances, etc.
- Regulatory agency meetings and interface at conferences
- Pharmaceutical manufacturer input, collaboration, feedback
- Evaluation of emerging regulatory trends in major global markets
geography.
Conclusion
When marketing a combination product globally, the importance of a collaborative relationship between pharmaceutical manufacturers and drug delivery technology providers cannot be overstated. To successfully work together, the two parties must have a collaborative infrastructure that is based on strategic alignment, proactive regulatory awareness, lifecycle support and continuous improvement globally, allowing the team to:
- Anticipate and overcome obstacles
- Streamline internal and external regulatory processes
- Avoid potential delays
Elena Mack possesses over 19 years experience in quality assurance and regulatory affairs. She has an extensive background in microbiology, manufacturing operations and regulatory affairs in biopharmaceutical, medical device (PMA/510K), liquids/semi-solids (Rx & OTC), contract manufacturing, cosmetic and aseptic processing environments. Elena holds three ASQ certifications—CQA, CMQOE and CPGP—a BSc in Microbiology from University of the Sciences in Philadelphia and a MSc in Quality Assurance & Regulatory Affairs from Temple University.
Kevin Lentz possesses over 20 years’ experience in regulatory affairs and quality assurance. He has an extensive background in medical device (wearable, implanted, delivery systems), tissue products and combination products regulatory affairs. Kevin holds a BSc in Physical Chemistry from York College of PA.