1. Brief statement of the general nature of the views you wish to present.
SUMMARY STATEMENT OF NATIONAL ELECTRICAL MANUFACTURERS ASSOCIATION ON COMBINATION PRODUCTS TO BE PRESENTED AT FDA PUBLIC HEARING – NOVEMBER 25, 2002
This is the summary statement of the National Electrical Manufacturers Association (NEMA) presentation to be given at the FDA public hearing on November 25, 2002 on combination products. The presentation of NEMA will address questions
# 2 through # 7 in the Federal Register notice, 67 F.R. 65801, October 28, 2002.
What factors should FDA consider in determining the primary mode of action of a combination product? In instances where the primary mode of action of the combination product cannot be determined with certainty, what other factors should the agency consider in assigning primary jurisdiction? Is there a hierarchy among these additional factors that should be considered in order to ensure adequate review and regulation (e.g. which component presents greater safety questions)?
FDA should consider the mode of action of a combination product on a case-by-case basis. Safety and effectiveness concerns should be considered separately for the components of a combination product, and, if need be, evaluated by separate Centers according to the location of the greatest expertise. For example, imaging contrast agents in magnetic resonance imaging and ultrasound present unique questions in these areas.
Review of the pharmacologic safety of these agents should be performed by CDER, where the expertise already exists. Device-related safety issues, such as ultrasound acoustic energy or MR magnetic field strengths and their effects, should be reviewed utilizing CDRH resources, due to their expertise in these aspects.
Review of the effectiveness of these agents should follow a similar distinction. NEMA believes that the effectiveness claims of the combination of an ultrasound or MR imaging system with a contrast agent are best reviewed by CDRH staff, where there exists a long history of adequate regulation of the entire range of imaging devices and their clinical performance. The addition of contrast agents to these applications does not constitute a significant change in the nature of the device’s effectiveness.
What are the general scientific and policy principles that should be followed in selecting the premarket regulatory authorities to be applied to combination products? Is one premarket review mechanism (e.g. premarket approval (PMA), premarket notification (510(k)), new drug application (NDA), or biologic licensing application (BLA)) more suitable than another for regulating combination products?
The premarket regulatory authorities applied to combination products should be those that normally govern applications for product clearance for the individual components. Where possible, the clearance process should proceed in parallel in order to help bring lifesaving technologies to market for the benefit of patients. That is, for devices, CDRH review mechanisms should apply, while CDER mechanisms should be used for drugs. For example, for use of ultrasound devices with contrast agents, the addition of ultrasound device clinical applications should be addressed through use of the 510(k) process, while in the case of drugs (contrast agents), the NDA process should be utilized. It should not be necessary to have additional indications for use simultaneously reviewed and approved for both the drug and device.
Recognizing the need to ensure product safety and effectiveness, what criteria should FDA use to determine whether a single application or separate applications for the individual components would be most appropriate for regulation of a combination product? For example, FDA may determine that it is necessary to apply elements of different regulatory authorities to a combination product to ensure safety and efficacy (e.g., device postmarketing reporting for the combination product, with drug current good manufacturing practices (CGMPs) applicable to the drug component only). Should the need to apply a mixed regulatory approach influence whether one application or two are more appropriate?
One of the key criteria to apply in determining whether single or separate applications should be submitted for the individual components of a combination product is the particular knowledge and experience of each center at FDA, i.e. CDRH, CDER, CBER, with the particular components comprising the combination product. Thus, this would imply separate applications for the individual components of a combination product. For example, questions concerning an innate property of the contrast agent should be addressed by CDER, since they have the highest level of knowledge and experience with specific questions concerning drugs, but do not have the same degree of expertise and experience with the review of devices.
What scientific and policy principles should be followed in determining the appropriate manufacturing and quality system regulatory authorities (e.g. Current Good Manufacturing Practices versus Quality System Regulation) applicable to combination products?
Analogous to the question of whether single or separate applications should be filed for combination products, NEMA believes that the Center having the knowledge and experience with the quality system regulatory process for a particular component of a combination product should apply the specific quality system process that is customarily used with that component. That is, device components of a combination product should utilize quality systems regulation, and drugs should be governed by CGMPs.
What scientific and policy principles should be followed in determining the appropriate adverse event reporting requirements (e.g. the drugs and biologics adverse event reporting system, Medical Device Reporting) to be applied to a combination product?
The adverse event reporting mechanism that applies to the specific facts of the adverse event should be utilized. Input from the user of the combination drug/device may be considered when determining whether the drug or device may have caused the event. For example, an adverse event involving a contrast agent, when used with an ultrasound or magnetic resonance device, should be reported by the component manufacturer that has received notice of the adverse event. This should be done using the reporting system that the manufacturer ordinarily uses. In cases where the root cause is unclear, a joint investigation by the drug and device manufacturer may be required and the subsequent results as to the cause of the event will direct the report to the appropriate Center.
What other comments do you have concerning other issues related to FDA regulation of combination products? (Examples may include cross labeling of products
Question 7. (Cont’d.)
intended to be used together, though manufactured by different companies; and application of promotion and advertising policies to combination products.)
In the instance of use of imaging devices used with previously approved contrast agents, FDA should permit device manufacturers to make general claims in their labeling about use of contrast agents with their devices. Since the action of a contrast agent enables the user to view the blood pool, a general claim to this effect should be permitted on the labeling of the imaging device. The device manufacturer would support this claim through provision of sample images in the course of the 510(k) process. The submission would demonstrate image performance, but, as always, it would be up to the clinician to make an actual diagnosis. The claim would simply be that the device, with use of the contrast agent, would allow visualization of blood flow in the body.
As a general policy, the “least burdensome” provision of FDAMA should be adhered to. Information that is not necessary to review of the device/drug combination should not be requested by the agency. Use of contrast agents with ultrasound and magnetic resonance devices represent significant technology advances which offer the prospect of better health care for patients and enhance diagnostic capabilities for the clinician. FDA should strive to assist in enabling these technologies to be offered to patients more widely. Marketing clearance should be granted to ultrasound devices with contrast agents permitting general indications for use which go beyond the present limited ultrasound clearance for Left Ventricular Opacification, along with the similar aforementioned magnetic resonance applications.
Clinical endpoints are often different for combination drug /devices than those seen for traditional drug products alone. In the cases of MR and ultrasound imaging contrast agents, they have no therapeutic effect nor are they intended to affect any bodily functions. They simply increase the signal to noise ratio of the blood pool in a diagnostic image beyond the typical range observed for the imaging device. Thus the review methods and approaches to required clinical data, outcomes, and endpoints are different than that traditionally requested by the FDA. Presently, the FDA process for reviewing of additional contrast clinical applications allows only the drug manufacturer to file a submission. FDA has imposed end point requirements that are not appropriate for drug/devices combinations that have no pharmacokinetic effect. Imaging device manufacturers have no regulatory means at their disposal to make a submission for additional clinical applications. For many years now this situation has prevented the clearance of these devices with agents for the diagnosis of difficult to image patients although such examinations are commonly in use worldwide. NEMA believes that a strategy needs to be developed that allows device manufacturers to clear new indications for use with contrast drugs that have already been approved for sale by the FDA.
2. The names and address of all persons who will participate in the presentation.
VP Quality and Regulatory Affairs
Philips Medical Systems
3. Approximate time that you request to make your presentation.
4. Special Accommodations required. Please specify.
Computer projector if possible