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Range of regulationsCompanies marketing medical devices in the UnitedStates (US) should have a clear understanding of therange of US regulations that apply to their products.Instead, some companies concentrate primarily oncomplying with the regulations related to the authorisa-tion process. Failure to comply with other applicableregulations can lead to delays in market introduction,increased costs related to regulatory enforcementactions, and possibly lost sales due to negative publicityresulting from US enforcement actions.Thus, it is criticalthat companies allocate the needed resources to developa comprehensive regulatory programme that identifiesand complies with all applicable US regulations.

The Food and Drug Administration (FDA) Center forDevices and Radiological Health (CDRH) maintains awebsite, Device Advice, (www.fda.gov/cdrh/devadvice)that provides a useful overview of US regulation ofmedical devices and radiation-emitting products withlinks to more detailed information. In contrast, theCDRH homepage (www.fda.gov/cdrh/) providesextensive and useful information on US medical deviceregulations and requirements, but sometimes over-whelms companies unfamiliar with US regulation.Some companies needing an introduction to theregulations find the Device Advice site easier tounderstand when initiating this effort.

After expending considerable effort to comply with United States (US)marketing authorisation regulations, a company launched its first product onthe US market. Unfortunately, the company failed to comply with otherapplicable US regulations, which led to a delay in the US product introductionand FDA postmarketing enforcement actions against the product.This articlediscusses ways that companies can prevent this from happening.

Dr Maria E. Donawa

physician, pathologist and pharmacist with more than 22 years’ regulatory experience, worked with the US FDA before becomingPresident of Donawa & Associates Ltd, an international consultancy firm, which provides clinical research, quality management system, regulatory affairs, and European Authorised Representative services to medical technology companies.

Maria Donawa

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SubmissionProcess

Image: DigitalVision

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Registration and listing Companies are sometimes surprised to learn that unlessthey have fulfilled US registration and listing require-ments, their products cannot be imported into the US.NonUS establishments must register, name a US agentand list their devices before exporting their medicaldevices to the US.The role of the US agent is discussedbelow.Therefore, companies need to complete theseprocesses in a timely fashion to avoid shipment anddistribution delays. No registration or listing feeis required.

The requirements for registration and listing aredescribed in US 21 Code of Federal Regulations (CFR)Part 807, Establishment Registration and Device Listingfor Manufacturers and Initial Importers of Devices.Registration and listing requirements apply tocompanies that ■ initiate or develop device specifications ■ manufacture a device for itself or for another person;however, a company that only manufactures devicesaccording to another company’s specifications, for com-mercial distribution by the company initiating specifica-tions, is not required to list those devices ■ repackage or relabel a device ■ act as initial importers■ manufacture components or accessories that areready to be used and packaged or labelled for commercialdistribution such as haemodialysis tubing or ophthalmiclens blanks.

The establishment registration process and instructionsfor completing the establishment registration formFDA-2891 are found at www.fda.gov/cdrh/devadvice/341.html The device listing process and instructions forcompleting the device listing form FDA-2892 are foundat www.fda.gov/cdrh/devadvice/342.html These formsmay be completed online, but must be printed andmailed to FDA. If an establishment is registering for thefirst time, the registration form must be mailed to FDAwith the medical device listing form.The establishmentregistration forms have been recently updated and obso-lete forms cannot be used. In addition to the informationprovided by the Device Advice site, registration andlisting information, including requirements applicableto nonUS establishments can be found at www.fda.gov/cdrh/reglistpage.html

Designating a US agentAs mentioned previously, nonUS establishments mustname a US agent before exporting their medical devicesto the US. These establishments must notify FDA of thename, address and phone number of their US agentwho must reside in the US or maintain a place of busi-ness in the US. In addition, the US agent cannot use apost office box as an address, cannot use an answeringservice and must be available to answer the phoneor have an employee available to answer the phoneduring normal business hours. The responsibilitiesof the US agent include

■ assisting FDA in communications with thenonUS establishment,■ responding to questions concerning the nonUSestablishment’s products that are imported or offeredfor import into the US ■ assisting FDA in scheduling inspections of theforeign establishment.

In addition, if FDA is unable to contact the foreignestablishment, FDA may provide information ordocuments to the US agent. If this is necessary, FDAwill consider this action equivalent to providing thatinformation or documents to the foreign establishment. Infuture, form FDA-2891(b) will be used for reporting USagent information; however, this form is not yet available.Therefore, nonUS establishments must notify FDA of itsUS agent by sending a letter to FDA.The information thatmust be provided and a sample letter can be found atwww.fda.gov/cdrh/devadvice/341.html#USA

If the nonUS establishment is registering for the firsttime, the registration form FDA-2891 should be mailedwith the US agent notification letter. FDA states that formsFDA-2891 or FDA-2892 cannot be used to identifya US agent.

Quality system regulationUnless exempt, manufacturers of medical devicesimported into the US must comply with the requirementsdescribed in 21 CFR Part 820, Quality System Regulation(QSR). Manufacturers are reminded of this obligationwhen they receive authorisation from FDA to markettheir products. In spite of this, some companies fail tofully comply with the QSR when they begin marketingtheir products in the US. In some cases, this is due to alack of awareness of the regulation because of inadequateresources being allocated to ensure awareness of, andcompliance with, applicable regulations. In other cases,companies believe that conformity with the Europeanquality system standards will suffice, which it does not.At times, inadequate resources are allocated for assessingcompliance needs and implementing required proce-dures. In any case, companies failing to fully complywith the QSR risk US enforcement actions if seriouscompliance failures become evident; this happens mostcommonly during FDA plant inspections. Problems canoccur when companies are forced to conduct last-minutecompliance assessments and institute rushed correctiveactions when notified of an imminent FDA plantinspection. For these reasons, companies need to beginplanning full compliance with the QSR as early aspossible so that this is achieved from the time that theirproducts enter the US market.This effort should alsoinclude a programme to evaluate and comply with FDArequirements for the control of electronic records andsignatures specified in 21 CFR Part 11. A guidancedocument that explains FDA’s current policies on theserequirements can be downloaded fromwww.fda.gov/cder/guidance/5667fnl.doc andwww.fda.gov/cder/guidance/5667fnl.pdf ➔

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LabellingAn understanding of European labelling requirements isinsufficient for ensuring compliance with US require-ments. Companies need to carefully review FDA labellingregulations and guidance documents before approvingfinal versions of labels and labelling materials for productsbeing shipped to the US. Failure to do so could lead toa costly product or labelling recall.Thus, companiesshould be aware that the requirements for medical devicelabelling are found in the following US regulations:■ General Device Labelling 21 CFR Part 801■ In Vitro Diagnostic Products 21 CFR Part 809■ Investigational Device Exemptions 21 CFR Part 812■ Good Manufacturing Practices 21 CFR Part 820■ General Electronic Products 21 CFR Part 1010

Links to these regulations and other information relatedto US labelling requirements can be found on the DeviceAdvice site at www.fda.gov/cdrh/devadvice/33.html

Medical Device ReportingIncidents in which a device may have caused or contributedto a death or serious injury must be reported to FDA underthe Medical Device Reporting (MDR) programme. Certaintypes of malfunctions must also be reported.The MDRrequirements are specified in 21 CFR Part 803.Althoughthere are similarities between the European and US require-ments for reporting adverse incidents, important differences

exist. For example, the European concept of a near incidentand its definition in European guidance documents is similarto, but not identical with, the US term “malfunction.” Inaddition, the timeframes for reporting incidents in Europediffers from that of the US. For this reason, companiesexporting to the US need to ensure that written proceduresspecifically cover US MDR requirements. Comprehensiveinformation on the MDR process can be found atwww.fda.gov/cdrh/devadvice/351.html

Corrections and removalsUnder 21 CFR 806, Medical Device Correction andRemovals, manufacturers and importers are required tosubmit a report to FDA of any correction or removal of amedical device if the correction or removal was initiatedto reduce a risk to health posed by the device or to rem-edy a violation of the Act caused by the device that maypresent a risk to health.

Companies should also be aware of US policies regard-ing recalls that are not related to risk to health. For exam-ple, in most cases, medical device recalls are voluntaryactions that manufacturers conduct under 21 CFR Part 7,Enforcement Policy. However, where a manufacturer orimporter fails to voluntarily recall a device that is a risk tohealth, FDA may issue a recall order to the manufacturerunder 21 CFR 810, Medical Device Recall Authority.

Information on FDA requirements and policies regard-ing medical device recalls and corrections and removalscan be found at www.fda.gov/cdrh/devadvice/51.html

Radiation-emitting productsCompanies that export medical devices that also emitradiation must meet specific requirements intended toprevent unnecessary exposure to radiation resulting fromthe use of these products.These requirements may includethe need to retain certain types of records and submissionof product reports to CDRH and are specified in 21 CFRParts 1000–1299.

The Device Advice site www.fda.gov/cdrh/devadvice/311.html includes the definition of “electronic productradiation,” examples of electronic products subject to FDAregulation, record and reporting requirements by producttype, guidance documents and labelling requirements.

Avoiding unnecessary risksCompanies must often expend considerable effort andresources when entering the US market.Therefore, anyrisks that could jeopardise the success of these projectsshould be avoided. Prudent companies will allocateadequate resources for identifying and complyingwith all applicable US regulations, not just those relatedto the submission process, to avoid those risks.

Maria E. Donawa

Donawa & Associates Ltd,

Via Fonte di Fauno 22, I-00153 Rome, Italy,

tel. +39 06 578 2665, fax +39 06 574 3786

e-mail: donawa@srd.it www.donawa.com

mdt

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