Introduction

Once the U.S. Food and Drug Administration (FDA or “the agency”) has cleared or approved a medical device for marketing in the United States, there are still significant postmarketing requirements with which medical device manufacturers must comply. These include labeling and advertising, Good Manufacturing Practices (GMPs), and postmarketing surveillance requirements such as adverse event reporting, among others. FDA uses various mechanisms to evaluate whether medical device manufacturers are complying with these requirements and takes enforcement actions against those that are not in compliance.

Establishment Registration and Device Listing

Medical device manufacturers are required to register each manufacturing establishment and submit an accompanying list of medical devices that are made there. Foreign manufacturers are additionally required to provide the name of a U.S. agent who will serve as the representative of the establishment as part of their registration. There is an annual fee for establishment registration. For fiscal year 2013, this fee is $2,575 (USD).

Labeling and Advertising

Medical device labeling must clearly inform a user about how to use the medical device. In many cases, the appropriate labeling for a device is predetermined by what is included, and thus reviewed by FDA, in the premarket submission (e.g., 510(k) submission or premarket approval application (PMA)). Labeling includes written materials that are sold with the product, such as user manuals and instruction sheets; it is important to note, however, that FDA’s definition of “labeling” also includes materials that are traditionally considered advertising, such as posters, pamphlets, brochures and web pages, among other items. Therefore, a medical device manufacturer must take care to ensure that all promotional and other materials associated with the medical device are consistent with, and do not differ in message or claims from, labeling materials included in the premarket submission. Additionally, medical devices that are manufactured in foreign countries are typically required to indicate the country of origin on the label.

Good Manufacturing Practices—Quality Systems Regulations

Medical devices must be manufactured in accordance with established GMP. GMP requirements for medical devices are outlined in the Quality Systems Regulation (QSR). These regulations require that a medical device manufacturer have a quality system for the design, manufacture, packaging, labeling, storage, installation and servicing of medical devices intended for commercial distribution in the United States. More specifically, the QSR requires various specifications and controls be established for devices; that devices be designed and manufactured under a quality system to meet these specifications; that finished devices meet these specifications; that devices be correctly installed, checked and serviced; that quality data be analyzed to identify and correct quality problems; and that complaints be processed. The details of any given manufacturer’s quality system will vary according to the risk presented by the device, the complexity of the device and manufacturing processes, and the size and complexity of the organization. Essentially, each quality system must be tailored to the specific device being manufactured, so that it can appropriately respond to the unique risks and issues raised by that device. Medical device software is subject to all parts of the QSR.

Special Controls

Some Class II medical devices—as a condition of their premarket clearance—are subject to special controls, which are requirements in addition to general controls (e.g., registration, listing, GMP, recordkeeping and reporting) that FDA deems are necessary to ensure the safety and effectiveness of a specific medical device or type of medical device. Special controls are typically defined by regulation and initially designed or designated during the premarket review process.

Postmarketing Surveillance

Postmarketing surveillance includes monitoring the safety of medical devices once those devices are being used in the marketplace. The most common postmarketing surveillance activity is medical device reporting, required of all medical device manufacturers, in accordance with the Medical Device Reporting (MDR) regulation. FDA requires medical device reporting so that safety issues can be identified and addressed quickly. When such issues are identified, FDA may require corrective actions—such as modifying labeling or instructions for use, improving user training or removing the device from the market—to ensure proper use or patient safety. Under the MDR regulation, FDA requires that manufacturers and importers report to FDA whenever the firm becomes aware of information that reasonably suggests that one of its marketed devices (1) has or may have caused or contributed to a death or serious injury; or (2) has malfunctioned and that a reoccurrence of the malfunction of the device (or similar device marketed by the manufacturer or importer) would be likely to contribute to a death or serious injury. Depending on the significance of the risk, these reports must be submitted within five business days or 30 calendar days.

Although postmarketing surveillance almost always includes MDR regulation compliance (some low-risk devices may be exempt), other activities are only required under certain circumstances, and usually only for high-risk devices (e.g., permanent or long-term implants, life-sustaining devices, etc.).  Postmarketing surveillance can also include the similar-sounding, but distinct, activity of postmarket surveillance (no “ing” after “postmarket”). Postmarket surveillance is required for certain high-risk devices and compels manufacturers to conduct studies to gather safety and efficacy data after the device is in use in the marketplace. FDA may also require, at its discretion and through the issuance of an order, that a medical device manufacturer implement a tracking system.

There are also two programs in development that will affect future postmarketing surveillance requirements for medical devices. Although not yet implemented, FDA is working on regulations to establish a Unique Device Identification system that would, in general, require each individual medical device to be labeled with a unique identifier, permitting identification of the device through distribution and use and, when required by FDA, include the lot or serial number. Finally, FDA’s Sentinel Initiative, initially devised as an active surveillance system for monitoring drugs using electronic data from healthcare information holders, is also being used to monitor other medical products, such as medical devices. The Sentinel Initiative is still being developed and piloted, so it is not yet clear what a manufacturer’s obligations will be or how the data collection might affect medical device manufacturers.

FDA Compliance and Enforcement

FDA evaluates and enforces postmarketing compliance through several mechanisms, including conducting inspections, issuing warning letters, requiring manufactures to correct or remove violative products from the marketplace and, in the most serious cases, seizing products, levying civil monetary penalties and imposing criminal penalties for manufacturers (potentially including prison sentences for corporate officers). FDA also enters into cooperative agreements with other countries to ensure that non-compliant products are refused entry into the United States.

Inspections can be scheduled or unannounced and will involve one or several officials from FDA visiting the manufacturing facility. During the visit, FDA will inspect the physical facility and records to verify compliance with all FDA requirements, especially GMP/QSR and recordkeeping requirements. The records review will include an evaluation of whether the manufacturer has made all appropriate reports to FDA. Typically, if FDA finds violations during the inspection, the agency will issue what is known as a “Form 483,” which will enumerate the observed violations and require a response from the manufacturer. If the manufacturer’s response is not satisfactory to FDA, then the agency may issue a Warning Letter, which is published on FDA’s website and requires a response from the manufacturer. If FDA finds serious or significant violations during an inspection, the agency may immediately issue a Warning Letter or take harsher enforcement actions accordingly. If a manufacturer refuses to take corrective actions in response to a Form 483 or Warning Letter, FDA will escalate its enforcement measures, which could include product seizure or, for foreign manufacturers, the refusal of product imports into the United States.

Compliance with Other U.S. Laws

In addition to ensuring compliance with FDA laws and regulations, medical device manufacturers also must determine whether other U.S. laws are applicable to their medical devices and ensure compliance with those laws as well. Most commonly, medical devices may also be subject to compliance with the laws and regulations of the U.S. Federal Trade Commission (FTC), Consumer Product Safety Commission (CPSC), U.S. Environmental Protection Agency (EPA) and, for products imported into the United States, U.S. Customs and Border Protection (CBP).

Special Considerations for Foreign Medical Device Firms

Regardless of whether a medical device is manufactured in the United States or in another country, it is subject to the same FDA premarket and postmarket compliance requirements. Any foreign establishment engaged in the manufacture, preparation, propagation, compounding or processing of a device imported into the United States, however, must identify a U.S. agent for that establishment, as part of the establishment registration process.

The inspection and enforcement environment for foreign manufacturers is slightly different than for those located in the United States. This is particularly the case for manufacturers located in China and India, which are subjected to additional scrutiny due to a history of non-compliance by a number of manufacturers in those countries. The result has been a dramatic increase in inspections administered through FDA's Office of International Programs (OIP) in conjunction with FDA's overseas offices. As a consequence, the number of detentions and other import disruptions has increased; we expect this trend to continue for some time.

Additionally, medical devices are subject to all regular U.S. laws and regulations for the importation of goods.

Conclusion

Although it can be challenging to develop and maintain a robust compliance program, investment in such a program is necessary for any company that plans to market their medical devices in the United States. Violations of FDA requirements can, in the most serious cases, result in product seizures, civil monetary penalties and criminal penalties for manufacturers (which can include prison sentences for corporate officers). Even when violations do not rise to such a level, non-compliance can result in a manufacturer being placed on an unofficial “bad actors” list that can make every interaction with the agency strained and contentious. In addition, such non-compliance can result in bad publicity, including near-certain coverage in the trade press. At the same time, a history of cooperativeness and compliance can go a long way to win favor with the agency, even when minor issues arise. Having a positive relationship and good compliance record with FDA thus becomes an important part of a company’s successful market operations in the United States.