Kim Ehman, WuXi AppTec Medical Device Testing07.19.22
Submitting combination products for regulatory review can be complex and confusing. According to the U.S. Food and Drug Administration (FDA), a combination product is composed of any mixture of drug, device, or biological product. Combination products fall into three distinct categories:
The regulatory submission process most commonly drives confusion about combination products. Determining which FDA center will review a combination product submission depends on several factors, including device type, its primary mode of action (PMOA), and geographic market. For a combination product, the PMOA is the single mode of action that provides the most important therapeutic action. Navigating multiple submission paths and regulatory fluidity can be challenging, but manufacturers and drug sponsors can take steps to strengthen submissions, shorten timelines, improve testing outcomes, and support patient safety.
When a device has two independent modes of action, and neither is subordinate to the other, the FDA uses an algorithm for determining center assignment. Manufacturers or drug sponsors that disagree with their product classification or its PMOA can submit a formal request for designation (RFD)—essentially asking the OCP to reconsider their product's classification or center assignment. There is also an informal, nonbinding version called a pre-RFD. In either case, manufacturers or sponsors can propose a change to their center assignment, leaving the OCP to make the final, formal determination. If the OCP does not provide feedback on the RFD within 60 days, the manufacturer/sponsor's proposed center assignment makes the final determination.
Each review center determines product classification, but preclinical safety testing for combination products is not fully defined in FDA documentation. This may require manufacturers or sponsors to adjust their approach and embrace outside-the-box thinking. Knowing reviewers' expectations can help manufacturers and sponsors prepare safety data and supporting information that will help them achieve regulatory success.
But standards can change so quickly that even recent biological safety evaluations may be outdated. In fact, the FDA published new premarket guidance for combination products in January this year. Clearly, fully supporting patient safety in combination products requires a comprehensive strategy. This includes chemical characterization, a toxicological risk assessment (TRA), and biocompatibility testing.
In drug-device or biologic-device combination products, the drug or biologic substance should be fully characterized (chemistry, mechanisms of action, safety profile), and the final product (drug- or biologic-device product) also needs to be characterized, which includes a complete biocompatibility and chemistry evaluation. Biocompatibility and chemical characterization studies can become complex, as some tests may be conducted with and without the drug or biologic (to demonstrate the drug or biologic’s potential impact on the device and vice versa). Thus, before initiating biocompatibility or chemical characterization studies, a test plan should be developed to determine which tests are applicable to the device only or to the final finished product.
Biocompatibility testing can address various potential hazards, including sensitization, irritation, and general toxicity; however, biocompatibility testing alone may not always sufficiently assess safety. Consistent with ISO 10993-1 (2018), chemical characterization testing (extractables and leachables testing), followed by a toxicological risk assessment (TRA) may address many biocompatibility endpoints, saving manufacturers both time and money. When a chemical characterization study is conducted properly, the TRA can address several biocompatibility endpoints, including short- and long-term toxicity risks, genotoxicity and carcinogenicity potential, as well as developmental and reproductive toxicity. This is done by evaluating each identified compound in the chemical characterization study and comparing an acceptable level to the estimated patient exposure.
Revised regulations and rigorous chemical and toxicological analyses mean toxicologists will likely find "equivocal" results—those for which there is insufficient data to support the TRA. This should not cause panic. When toxicologists find equivocal results, they can conduct targeted analyses and simulated-use studies to help mitigate risk and further demonstrate product safety.
When teams lack in-house expertise, collaborating with partners that have deep technical and regulatory experience can be invaluable. Reliable laboratory testing partners fill in where internal expertise is limited and collaborate to develop the strongest possible submission.
Laboratory partners can also provide a bridge between manufacturers and regulators. Some lab partners have staff that serves on regulatory boards and have unique insight into evolving guidance and information. Another advantage to working with technical partners is their guidance during and after pre-submission meetings with the FDA.
Pre-submission meetings are informal touchpoints with the agency that provide opportunities to discuss a device or drug delivery system and gather feedback. Regulators can answer outstanding questions and confirm submission expectations that might impact a product's biological evaluation. The meetings are usually limited to an hour per device, but they can provide critical information early enough for manufacturers to make fundamental decisions about the path forward. Lab testing partners can also partake in pre-submission meetings to provide valuable counsel to manufacturers and sponsors.
Pre-submission meetings are available for every product, and the FDA recommends manufacturers and sponsors take advantage of them. However, cross-labeled combination products raise distinct considerations. Cross-labeled products often involve filing a new drug application for the drug and premarket notification 510(k) for the device. Despite filing separate submissions, manufacturers and sponsors should continue using their originally dedicated review center for all correspondence. The original review center is responsible for ensuring that representatives from the necessary centers, including the OCP, have conducted premarket product reviews and will attend pre-submission meetings.
Once manufacturers and sponsors understand their device's category and submission pathway, they can tailor their study design to fit their reviewer's requirements. This is another area in which a trusted laboratory testing partner can provide great value.
The complexity of combination product submissions magnifies the importance of correct study design. Multiple centers will request varying endpoints, specific regulatory standards will apply to certain products, and reams of documentation will be used to justify the product's analytical approach. This information should be contained in a drug master file (DMF). DMFs provide confidential, detailed information about facilities, processes, or articles used to manufacture, process, package, and store human drug products. Lab testing partners can ensure efficient and thorough information gathering, organizing and sharing.
Despite this, device manufacturers and drug sponsors should not feel alone in the submission process. Testing partners offering advanced equipment, impeccable credentials, and firsthand knowledge of the regulatory landscape can provide peace of mind and deliver regulatory success.
Dr. Kim Ehman, Ph.D., DABT, is technical director of Regulatory Toxicology, with a focus on medical device and combination products. Dr. Ehman has more than 18 years of toxicology and medical device experience, with expertise in toxicological risk assessments for medical devices, food and beverage products, and electronic nicotine delivery systems. Before joining WuXi AppTec Medical Device Testing, she worked as a toxicologist for RTI International, Toxicology Regulatory Services, and Altria Client Services. She earned her Ph.D. in parasitology from McGill University and conducted postdoctoral research at the U.S. EPA in developmental neurotoxicology. In her current position, Dr. Ehman provides medical device manufacturers and suppliers with technical and regulatory support for biocompatibility test programs and conducts quantitative toxicological risk assessments to support product safety and risk management decisions. She earned a B.Sc. degree in biology from Seton Hall University.
- Single-entity products consist of two or more regulated components that are physically, chemically, or otherwise combined and produced as a single entity. Drug-eluting stents, transdermal patches, EpiPens, and metered dose inhalers are all single-entity products.
- Co-packaged products consist 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. Drugs or vaccines packaged with a syringe, surgical trays with instruments, and first aid kits containing bandages, gauze, antibiotics, and ointments are considered co-packaged.
- Cross-labeled products are drugs, devices, or biologics packaged separately but, according to their labeling, are intended for use only with another approved drug, device, or biological product. Combinations of investigational drugs, devices, or biological products also qualify here. A photosensitizing drug with an activating laser/light source would be considered cross-labeled.
The regulatory submission process most commonly drives confusion about combination products. Determining which FDA center will review a combination product submission depends on several factors, including device type, its primary mode of action (PMOA), and geographic market. For a combination product, the PMOA is the single mode of action that provides the most important therapeutic action. Navigating multiple submission paths and regulatory fluidity can be challenging, but manufacturers and drug sponsors can take steps to strengthen submissions, shorten timelines, improve testing outcomes, and support patient safety.
Determining the Primary Reviewer
The FDA's Office of Combination Products (OCP) classifies medical products as devices, drugs, biologics, or combination products, and assigns them to review centers. The OCP also serves as the primary point of contact between the agency and industry. A product's PMOA determines which regulatory center has primary jurisdiction and will ultimately serve as the lead reviewer.- Device-led products: Products whose PMOA is dependent on a device will submit to the Center for Devices and Radiological Health (CDRH), which oversees medical devices and safe radiation-emitting products. A drug-eluting stent, for example, is a CDRH-regulated device. The stent keeps the artery open, which is the device's primary function. The drug plays a vital role in preventing blood clots and mitigating side effects like irritation or inflammation, but the product’s most important therapeutic action is the stent, not the drug.
- Drug-led products: Products whose PMOA is dependent on a drug will submit to the Center for Drug Evaluation and Research (CDER), which oversees prescription, over-the-counter and generic drugs. This includes medication, fluoride toothpaste, antiperspirants, dandruff shampoo, and sunscreen. An EpiPen is a CDER-regulated device, as the drug constricts blood vessels, increases blood pressure, and decreases the swelling from allergic reactions. The injector administers medication, but epinephrine is the life-saving drug that prevents anaphylaxis.
- Biologic-led products: Products whose PMOA depends on biologics and related products (i.e., vaccines, live biotherapeutics, blood products) will submit to the Center for Biologics Evaluation and Research (CBER), which oversees medical devices used for cellular/gene therapies, tissue products and blood collection, screening, and processing. An anticoagulant is a CBER-regulated device because it is a biologic that helps prevent blood clots and reduces the chances of strokes and heart attacks.
When a device has two independent modes of action, and neither is subordinate to the other, the FDA uses an algorithm for determining center assignment. Manufacturers or drug sponsors that disagree with their product classification or its PMOA can submit a formal request for designation (RFD)—essentially asking the OCP to reconsider their product's classification or center assignment. There is also an informal, nonbinding version called a pre-RFD. In either case, manufacturers or sponsors can propose a change to their center assignment, leaving the OCP to make the final, formal determination. If the OCP does not provide feedback on the RFD within 60 days, the manufacturer/sponsor's proposed center assignment makes the final determination.
Each review center determines product classification, but preclinical safety testing for combination products is not fully defined in FDA documentation. This may require manufacturers or sponsors to adjust their approach and embrace outside-the-box thinking. Knowing reviewers' expectations can help manufacturers and sponsors prepare safety data and supporting information that will help them achieve regulatory success.
Biological Evaluations of Combination Product
A complete biological evaluation should identify a product’s biocompatibility. The International Organization for Standardization (ISO) published a revision to 10993-18 in 2020 and is scheduled to revise 10993-17 this year. Together, the two standards provide approaches for robustly evaluating devices in order to characterize potential risks, and directly impact combination products.But standards can change so quickly that even recent biological safety evaluations may be outdated. In fact, the FDA published new premarket guidance for combination products in January this year. Clearly, fully supporting patient safety in combination products requires a comprehensive strategy. This includes chemical characterization, a toxicological risk assessment (TRA), and biocompatibility testing.
In drug-device or biologic-device combination products, the drug or biologic substance should be fully characterized (chemistry, mechanisms of action, safety profile), and the final product (drug- or biologic-device product) also needs to be characterized, which includes a complete biocompatibility and chemistry evaluation. Biocompatibility and chemical characterization studies can become complex, as some tests may be conducted with and without the drug or biologic (to demonstrate the drug or biologic’s potential impact on the device and vice versa). Thus, before initiating biocompatibility or chemical characterization studies, a test plan should be developed to determine which tests are applicable to the device only or to the final finished product.
Biocompatibility testing can address various potential hazards, including sensitization, irritation, and general toxicity; however, biocompatibility testing alone may not always sufficiently assess safety. Consistent with ISO 10993-1 (2018), chemical characterization testing (extractables and leachables testing), followed by a toxicological risk assessment (TRA) may address many biocompatibility endpoints, saving manufacturers both time and money. When a chemical characterization study is conducted properly, the TRA can address several biocompatibility endpoints, including short- and long-term toxicity risks, genotoxicity and carcinogenicity potential, as well as developmental and reproductive toxicity. This is done by evaluating each identified compound in the chemical characterization study and comparing an acceptable level to the estimated patient exposure.
Revised regulations and rigorous chemical and toxicological analyses mean toxicologists will likely find "equivocal" results—those for which there is insufficient data to support the TRA. This should not cause panic. When toxicologists find equivocal results, they can conduct targeted analyses and simulated-use studies to help mitigate risk and further demonstrate product safety.
Partnering With Experts
Combination products are complex, and the regulatory process can be arduous. Manufacturers should be prepared for a lengthier timeline than they are used to, given the level to which the drug, device, biologic, production, and packaging environments will be analyzed. The expertise, equipment, and database needed to comply with evolving ISO standards can present additional challenges. But manufacturers and sponsors do not have to face these hurdles alone.When teams lack in-house expertise, collaborating with partners that have deep technical and regulatory experience can be invaluable. Reliable laboratory testing partners fill in where internal expertise is limited and collaborate to develop the strongest possible submission.
Laboratory partners can also provide a bridge between manufacturers and regulators. Some lab partners have staff that serves on regulatory boards and have unique insight into evolving guidance and information. Another advantage to working with technical partners is their guidance during and after pre-submission meetings with the FDA.
Pre-submission meetings are informal touchpoints with the agency that provide opportunities to discuss a device or drug delivery system and gather feedback. Regulators can answer outstanding questions and confirm submission expectations that might impact a product's biological evaluation. The meetings are usually limited to an hour per device, but they can provide critical information early enough for manufacturers to make fundamental decisions about the path forward. Lab testing partners can also partake in pre-submission meetings to provide valuable counsel to manufacturers and sponsors.
Pre-submission meetings are available for every product, and the FDA recommends manufacturers and sponsors take advantage of them. However, cross-labeled combination products raise distinct considerations. Cross-labeled products often involve filing a new drug application for the drug and premarket notification 510(k) for the device. Despite filing separate submissions, manufacturers and sponsors should continue using their originally dedicated review center for all correspondence. The original review center is responsible for ensuring that representatives from the necessary centers, including the OCP, have conducted premarket product reviews and will attend pre-submission meetings.
Once manufacturers and sponsors understand their device's category and submission pathway, they can tailor their study design to fit their reviewer's requirements. This is another area in which a trusted laboratory testing partner can provide great value.
The complexity of combination product submissions magnifies the importance of correct study design. Multiple centers will request varying endpoints, specific regulatory standards will apply to certain products, and reams of documentation will be used to justify the product's analytical approach. This information should be contained in a drug master file (DMF). DMFs provide confidential, detailed information about facilities, processes, or articles used to manufacture, process, package, and store human drug products. Lab testing partners can ensure efficient and thorough information gathering, organizing and sharing.
A Final Word
Understanding the regulatory journey for medical devices and drug delivery systems can be intimidating. Regulatory standards continuously evolve, rendering recent submission data obsolete and intensifying or changing the analytical approach. Determining which FDA center will review a combination product—and delivering the requisite data—is another aspect that may require a bit of guidance. Additionally, regulators now expect detailed chemical and toxicological data.Despite this, device manufacturers and drug sponsors should not feel alone in the submission process. Testing partners offering advanced equipment, impeccable credentials, and firsthand knowledge of the regulatory landscape can provide peace of mind and deliver regulatory success.
Dr. Kim Ehman, Ph.D., DABT, is technical director of Regulatory Toxicology, with a focus on medical device and combination products. Dr. Ehman has more than 18 years of toxicology and medical device experience, with expertise in toxicological risk assessments for medical devices, food and beverage products, and electronic nicotine delivery systems. Before joining WuXi AppTec Medical Device Testing, she worked as a toxicologist for RTI International, Toxicology Regulatory Services, and Altria Client Services. She earned her Ph.D. in parasitology from McGill University and conducted postdoctoral research at the U.S. EPA in developmental neurotoxicology. In her current position, Dr. Ehman provides medical device manufacturers and suppliers with technical and regulatory support for biocompatibility test programs and conducts quantitative toxicological risk assessments to support product safety and risk management decisions. She earned a B.Sc. degree in biology from Seton Hall University.
