November 2002 / Volume 47 / Number 11 / Page 1334
Bringing New Nebulizer Technologies to Market: Regulatory Issues
Regulatory ResponsibilitiesThis review outlines regulatory issues involved in bringing new nebulizer technologies to market and describes the regulatory roles of the Center for Devices and Radiologic Health and the Center for Drug Evaluation and Research. The responsible agency is determined by whether a new device involves a new drug formulation.
Center for Devices and Radiologic Health
Center for Drug Evaluation and Research
Ordinarily, an application supporting the approval of a new nebulizer would be reviewed by the Center for Devices and Radiologic Health (CDRH) under section 510(k) of the Food, Drug, and Cosmetics Act, under which a nebulizer is a class II device. This means that the application must demonstrate that the new device is substantially similar to a previously available product (called a "predicate" device) in its performance and other key attributes.
However, there has been increasing development of novel nebulization systems that require specific drug formulations, with or without specific containers (eg, a cartridge that is sold only for and fits only in the device being developed). Often these formulations and containers are not otherwise approved and available. When a new nebulizer requires the development of a new drug/device product (ie, the specific formulation and/or its unique container), the regulation of the new drug/device combination would ordinarily occur through the Center for Drug Evaluation and Research (CDER) under the New Drug Application regulations.
This review does not specifically address biologic products administered via nebulization; generally such products and their administration systems would be reviewed through the Center for Biologics Evaluation.
- A pharmaceutical company develops a hand-held nebulizer to deliver a unique formulation of ipratropium bromide.1 Because the product does not use available unit-dose nebules of ipratropium, but instead contains a unique formulation, it would be considered a new drug/device combination and would ordinarily be developed and reviewed under CDER and drug regulations. From a regulatory standpoint this is similar to how new metered-dose inhalers (MDIs) and dry-powder inhalers (DPI) are treated.
- A new nebulizer technology is developed to deliver medication from standard plastic unit-dose vials. Such a new device would be handled by CDRH under the 510(k) regulation, since no new drug product would be developed. This example assumes the new device is intended to administer the drug in a manner consistent with instructions in the drug label and that there is no claim of unique clinical benefit from the drug administered via the new device.
- A new nebulizer is intended to be used with an existing marketed drug, but the new nebulizer uses a different amount of drug than indicated in the marketed drug's label instructions. In this instance the labeling of the marketed drug would need to be changed, and the product would be a combination product (see the United States Code of Federal Regulations, at 21 CFR 3.2(e)(3)).2 Because the primary mode of action of the combination product is as a drug, CDER would normally be the agency with primary jurisdiction over the combination product.
Center for Devices and Radiologic Health
Chapter 21 of the Code of Federal Regulations contains all the rules by which the United States Food and Drug Administration (FDA) implements the Food, Drug, and Cosmetics Act, which is the law that, in part, authorizes the FDA to regulate new drugs and devices. These regulations are binding on the industry as well as the FDA. The regulatory definition of a nebulizer (21 CFR 868.5630) reads:
a) Identification. A nebulizer is a device intended to spray liquids in an aerosol form into gases that are delivered directly to the patient for breathing. Heated, ultrasonic, gas, venturi, and refillable nebulizers are included in this generic type of device.
As such, products meeting that general definition that are able to use existing, marketed drug formulations in a manner consistent with the labeling of the formulations would be reviewed under the device law and regulations. Nebulizers are generally regarded as fitting under section 510(k), under which the sponsor must show that the device is substantially equivalent to a predicate device (ie, a previously marketed nebulizer). The focus of the application and of its review is the in vitro characterization of the nebulizer and its output and the comparison of the in vitro data to those of the predicate device. Device performance elements that must be studied and presented in the application include in vitro testing that focuses on comparative characterization of aerosol emitted from the mouthpiece, including total mass emitted, mass median aerodynamic diameter, geometric standard deviation, and particle size distribution. Biocompatibility testing of the materials may also apply.
Characterization data supporting a new nebulizer are usually acquired via in vitro studies done under nonclinical "Good Laboratory Practice" conditions. The resulting reports should detail the protocols and instruments used, the validation used, and any statistical and clinical considerations for these tests.
Center for Drug Evaluation and Research
If a new nebulizer is considered a new drug/device combination, it would ordinarily be reviewed by CDER, since the primary mode of action is as a drug. Relevant drug laws and regulations are found in section 505 of the Food, Drug, and Cosmetics Act and in 21 CFR 312 and 314. In this case there is no requirement that the nebulizer be equivalent to a predicate nebulizer. As stated above, the development and review for such a product would be very similar to review of a new MDI or DPI. Though it is possible that the entire application would be reviewed by CDER staff, depending on the complexity and novelty of the device proposed, some aspects of the device review may be consulted to CDRH, including electronic circuitry, software, or other novel aspects.
Though it is beyond the scope of this review to detail the expectations for a development program for a new nebulizer (representing a new drug/device combination), the general elements that would need to be addressed in a New Drug Application for such a device include:
- Full characterization of performance in vitro
- In vitro ruggedness testing; life-cycle performance testing
- Pharmacokinetics and pharmacodynamics data with the "to-be-marketed" device (ie, the device used in late-phase studies should be substantially the same in performance and important features as that proposed for marketing)
- Efficacy and safety data with the to-be-marketed device
- Performance in clinical studies, including testing of devices returned for failure and testing of a portion of devices at end of trial for in vitro performance
New nebulizer technologies may be reviewed by CDRH, CDER, or both, depending on the specifics of the device, its novelty, and whether it requires a new drug formulation or container. Whether developed and reviewed under the device regulations or the new drug regulations, sponsors must adequately characterize the device performance to assure its characteristics and attributes, and, in some cases, to assure its performance over time.
For those seeking more information, there are a number of helpful Web pages:
For general issues related to CDRH review of nebulizers: http://www.fda.gov/cdrh/ode/784.html
For issues related to incorporation of software into devices: www.fda.gov/cdrh/ode/57.html
For general issues related to MDIs and DPIs, much of which may be useful to a new device/drug combination: http://www.fda.gov/cder/guidance/2180dft.htm
For issues related to new drugs for nebulization: http://www.fda.gov/cder/guidance/4234fnl.htm
- Iacono P, Velicitat P, Guemas E, Leclerc V, Thebault JJ. Improved delivery of ipratropium bromide using Respimat (a new soft mist inhaler) compared with a conventional metered dose inhaler: cumulative dose response study in patients with COPD. Respir Med 2000;94(5):490-495.
- United States Code of Federal Regulations. Available at: http://www.access.gpo.gov/nara/cfr/index.html.
Robert J Meyer MD is affiliated with the Office of Drug Evaluation, Center for Drug Evaluation and Research, United States Food and Drug Administration, Rockville, Maryland.
*Disclaimer: This review represents the opinions and observations of Robert J Meyer MD, based on his expertise and experience, and is not intended to relay official policy of the United States Food and Drug Administration. The contents of this review should not be regarded as binding on the industry or on the Food and Drug Administration.
This report was prepared by Robert J Meyer MD for the 30th RESPIRATORY CARE Journal Conference, Liquid Nebulization: Emerging Technologies, held June 28-30, 2002, in Montréal, Québec, Canada. On short notice and unavoidably, Dr Meyer was unable to attend the conference. Thus, although the present report appears in the order it was to be presented at the conference, it is not accompanied by a discussion section.
Correspondence: Robert J Meyer MD, Office of Drug Evaluation II, HFD-102, Center for Drug Evaluation and Research, United States Food and Drug Administration, Parklawn Building, 5600 Fishers Lane, Rockville MD 20857.