17 July, 2012 Mark D. Kramer, President, Regulatory Strategies, Inc.
The views expressed in this article are those of the authors and do not necessarily represent those of their respective employers, GxP Lifeline, its editor or MasterControl, Inc.
Combination products raise a variety of regulatory challenges. In addition to the unique technological and scientific challenges these products may raise, when drugs and devices, drugs and biologics or devices and biologics are combined to create a new product, consideration must be given to what regulatory requirements will apply to the combination product as a whole. This article explains the key principles and processes established for the assignment, premarket review, and postmarket regulation of combination products in the United States.
"When there are no other combination products that present similar questions of safety and effectiveness with regard to the combination product as a whole, FDA assigns the product to the agency component with the most expertise related to the most significant safety and effectiveness questions presented by the combination product. For example, if the most significant safety and effectiveness issues presented by a drug-device combination product in this scenario were attributable to the drug constituent part, the combination product would likely be assigned to CDER."
A "combination product" is a drug-device, drug-biologic, device-biologic or drug-device-biologic product where the individual components (called "constituent parts") are:
- physically or chemically combined to create a single product (such as a drug-coated device, prefilled syringe, or drug-biologic conjugate);
- separate products packaged together (such as a convenience kit comprised of a catheter and anesthetic jelly); or
- products that are separately provided but labeled for use together (such as a photosensitive drug and light source). The United States is unusual in considering this type of concurrent use of separate products to be a combination product.
To address the perception that combination products often "fell through the cracks" between the three medical product centers (CBER, CDER and CDRH), in 2002 Congress mandated that FDA establish the Office of Combination Products (OCP). This small office, organizationally located in FDA's Office of the Commissioner, has several key functions to help clarify the regulatory challenges (see Figure 1). OCP's key roles are to serve as FDA's "traffic cop," determining which FDA Center will lead the review process for combination as well as non-combination products; to oversee the timeliness of combination product reviews (however, primary responsibility resides with the lead center to which the product is assigned); to serve as a resource for industry and FDA staff on combination product issues; and to develop policy and regulations to clarify combination product issues.Figure 1
A key early accomplishment of OCP was to publish a regulation clarifying how combination products are assigned to agency centers. As early as 1990, the law provided that FDA assign a combination product to a lead agency center based on the "primary mode of action" (PMOA) of the combination product, but beyond those four words, there was little clarity on just what PMOA meant. Furthermore, over time, FDA realized there were some combination products that did not have a clearly definable PMOA. To address these concerns, FDA set out definitions of mode of action and PMOA, as well as an "assignment algorithm" (see Figure 2) used to determine center assignment when the PMOA cannot be determined with reasonable certainty. The flowchart below provides an overview of the assignment process.Figure 2
"Mode of action" is the means by which a product achieves an intended therapeutic effect or action. "PMOA" is "the single mode of action of a combination product that provides the most important therapeutic action of the combination product." Looked at another way, PMOA is the "mode of action expected to make the greatest contribution to the overall intended therapeutic effects of the combination product." For example, if the PMOA of a drug-device combination product is attributable to its device constituent part, CDRH would have primary jurisdiction for the combination product, whereas if the PMOA of a drug-device combination product is attributable to its drug constituent part, CDER would have primary jurisdiction.
In cases where FDA is unable to determine the most important therapeutic action with reasonable certainty, an "assignment algorithm" is used. First, FDA looks at historical precedents to assign the combination product to the agency component that regulates other combination products that present similar questions of safety and effectiveness with regard to the combination product as a whole. When there are no other combination products that present similar questions of safety and effectiveness with regard to the combination product as a whole, FDA assigns the product to the agency component with the most expertise related to the most significant safety and effectiveness questions presented by the combination product. For example, if the most significant safety and effectiveness issues presented by a drug-device combination product in this scenario were attributable to the drug constituent part, the combination product would likely be assigned to CDER.
The formal process for determining combination product assignment is called a "Request for Designation." This brief submission, limited to 15 pages by regulation, must clearly explain your product and its composition, its intended use, how your product works, its PMOA, any data to substantiate the PMOA, and your recommendation for product assignment. The graphic below (see Figure 3) illustrates how combination products have been assigned over the last several years.Figure 3
Another early OCP accomplishment was to develop an SOP governing the consultation process that is used by FDA's centers to work together on premarket reviews of combination products. The SOP established the policy that "consults count," meaning that review timeframes for consultative reviews are just as important as the primary work for which a reviewer may be assigned. The SOP also outlines OCP's role in overseeing the timeliness of combination product reviews and the consultation process. The number of consultative reviews has grown to over 400 in a typical year, and the consultation process is more timely and predictable than before the SOP was established.
Most combination products (particularly combinations where the two components are physically combined to create a single product) are reviewed under a single marketing application, typically the type of application commonly submitted to the lead center (NDA, ANDA or BLA to CDER, BLA to CBER, 510(k) or PMA to CDRH). Some combinations, particularly cross-labeled products, may have separate applications covering the various components of the product (e.g, NDA for drug component and a 510(k) or PMA for device component). In some cases, FDA may require separate applications for the individual constituent parts of the combination, while in others, especially where separate sponsors exist for each 'half' of the product, the companies themselves may prefer separate applications for intellectual property or other business reasons.
One issue that sometimes arises is whether a combination product can be reviewed under the 510(k) process. While many combination products such as wound dressings and drug-coated catheters have been cleared under the 510(k) process, generally FDA will require a PMA for a combination product assigned to CDRH when the drug has not been previously approved under an NDA.
In late 2009, FDA published two proposed rules, not yet in effect, that would create new requirements for GMPs and postmarket adverse event reporting for combination products. A similar framework underlies both proposed rules and sets forth FDA's view that drugs, devices, and biological products do not lose their individual regulatory identities when they become constituent parts of a combination product. Under this framework, the GMP and postmarket safety reporting requirements specific to each constituent part of a combination product also apply to the combination product itself. However, rather than impose duplicative requirements for manufacturers to fully comply with both sets of requirements, the proposed rules set out a streamlined framework whereby a manufacturer would comply with one primary set of requirements, as well as specific, additional provisions to ensure that any unique requirements attributable to the "other" component are not lost if the product were to comply with only one set of requirements.
For GMPs, the proposed rule recognizes the similarities between the drug GMP requirements under 21 CFR 210 and 211 and the Quality System Regulation for devices under 21 CFR 820, but also identifies unique provisions in each set of regulations that must be preserved regardless of which set of regulations is primarily implemented. As an alternative to fully complying with both sets of requirements, a manufacturer could choose to follow a streamlined approach and operate under and comply with either 21 CFR 210 and 211 or 21 CFR 820, rather than both, provided that additional specific aspects of the other GMP framework are also incorporated (see Figure 4). Figure 4
Key Provisions of Quality System Regulation to be Implemented if Following 21 CFR 210/211
- 820.20 Management responsibility
- 820.30 Design controls
- 820.50 Purchasing controls
- 820.100 Corrective and preventive action
- 820.170 Installation
- 820.200 Servicing
Key Provisions of Drug GMPs to be Implemented if Following 21 CFR 820
- 211.84 Testing and approval/rejection of components, drug product containers & closures
- 211.103 Calculation of yield
- 211.132 Tamper-evident packaging for over-the-counter (OTC) human drug products
- 211.137 Expiration dating
- 211.165 Testing and release for distribution
- 211.166 Stability testing
- 211.167 Special testing requirements
- 211.170 Reserve samples
For postmarket reporting, the proposed rule recognizes that the individual regulations for drugs, devices, and biological products each require reports of death and serious adverse events; each provides for periodic and follow-up reports; and each provides a method to signal certain types of safety events that warrant expedited reporting. Despite these similarities, each set of regulations also has certain reporting standards and timeframes with unique requirements based upon the characteristics of the products for which the regulations were designed. For example, the drug reporting provisions have no requirement analogous to device malfunction reporting, while the device reporting provisions have no requirement analogous to drug three-day Field Alert Reporting. The intent of the proposed rule is to consolidate the requirements so that a combination product is subject primarily to the reporting requirements associated with the type of marketing application under which the product is approved or cleared, while at the same time ensuring that the public health benefit of the specific unique provisions is not lost if the combination product were subject solely to the reporting requirements associated with the type of marketing application (see Figure 5).Figure 5
Medical Device Reporting Provisions to be Implemented if Following Drug/Biologic Reporting
- 5-Day Report
- 30-Day Device Malfunction Report
Drug Reporting Provisions to be Implemented if Following Device Reporting
- 15-Day Alert Report
- 3-Day Field Alert Report
Biologic Reporting Provisions to be Implemented if Following Device or Drug Reporting
- 15-Day Alert Report (analogous to 314.80(c)(1)and(e))
- Expedited Blood Fatality Report
While drug, device, and biological product regulations share many similarities, each set of regulations emerged at different times and for different purposes and a number of differences exist that raise questions for how combination products are handled. While significant progress has been made at clarifying the issues that arise most frequently, such as assignment, premarket review, GMPs, and postmarket reporting discussed above, many issues remain. Sponsors will often benefit by communicating with the agency early and throughout the development process in order to help avoid surprises and ensure the most efficient regulatory development process.
Mark D. Kramer, RAC, is President, Regulatory Strategies, Inc. (www.regulatorystrategies.net), a regulatory consultancy specializing in medical devices and combination products. He has more than 25 years' experience in regulatory affairs, including 17 years at the U.S. Food and Drug Administration, culminating in his position as Director of FDA's Office of Combination Products from 2002 to 2007. From 2007-2010, Mark was Vice President, Regulatory Affairs, and Chief Regulatory Strategist at GE Healthcare, where he had executive responsibility for U.S., Canadian, and Latin American regulatory affairs for the medical device business. Mark is on the Board of Directors of the Regulatory Affairs Professional Society (RAPS), served as Chair of the Wisconsin RAPS Chapter from 2007-2010, and is an adjunct faculty member for St. Cloud State University's Master's program in regulatory affairs. Mark can be reached at firstname.lastname@example.org.