52 Practical Dermatology April 2008

Generally speaking, the word “device” almostalways conjures images of a mechanical con-traption. Asked just a few years ago to list the“devices” they use regularly in the clinic, manydermatologists would have named laser systems,

microdermabrasion machines, UV lightboxes, Unna boots,punch biopsy instruments, and even hand-held communica-

tions tools. But when a new generation of topical therapies foratopic dermatitis emerged with FDA clearance for marketing asdevices, many dermatologists were taken aback.

These agents garnered significant attention for their appar-ently unusual journey to market, but the reality is that numer-ous similar topical dressings were already on the market and inuse by dermatologists. Additional similar products are likely to

Breaking through confusion to uncover the facts aboutFDA regulations for various marketed products.

By Joseph Bikowski, MD and Bobbi Drais, MS, RAC

Ap[ril 2008 Practical Dermatology 53

emerge. To help clinicians understand the meaning of deviceclearance, the following review provides a look at current FDApolicies and procedures.

Avenues to MarketMedical products under the purview of the FDA—drugs,devices, and cosmetics—ultimately reach the US market via sev-eral distinct pathways, depending on their classification andintended use. A drug is essentially any article intended for use inthe diagnosis, cure, mitigation, treatment, or prevention of dis-ease. Drugs encompass any article intended to affect the struc-ture or any function of the body. A drug achieves its primaryintended purposes through chemical action within or on thebody and may be dependent upon being metabolized for theachievement of any of its primary intended purposes.

A device is similarly defined with an important distinction:its primary action is not achieved through a chemical action ormetabolism. A device is any instrument, apparatus, machine,implant, in vitro reagent, or component part or accessory that isintended for use in the diagnosis of disease or other conditions,or in the cure, mitigation, treatment, or prevention of disease. Adevice is intended to affect the structure or any function of thebody, but it does not achieve any of its primary intended pur-poses through chemical action within or on the body and is notdependent upon being metabolized for the achievement of anyof its primary intended purposes.

FDA oversees two medical product categories that do notrequire market “approval”: over-the-counter (OTC) drugs andcosmetics. Note that unlike drugs and devices, cosmetics do notalter the structure or function of the body. Their intended use isfor cleansing, beautifying, promoting attractiveness or alteringappearance. Over-the-counter drugs must adhere to an OTCmonograph, which outlines requirements for labeling and test-ing of these agents. The same general manufacturing principalsthat guide NDA and ANDA products guide the production ofOTC drugs.

Drugs reach the market upon approval of a new drug appli-cation (NDA) or, in the case of generic equivalents for approveddrugs, an abbreviated new drug application (ANDA). Thisprocess applies to any new chemical entity, formulation, or indi-cation. As part of the review and approval process, the agencyacquires and reviews information and data from the applicationsponsor, including but not limited to data from clinical trials inhumans. Most dermatologists are quite familiar with thenumerous components of this costly and lengthy process.

Similar to the drug approval process, the biologics licensingprocess applies to any biologically-based therapeutic agent,whether it be blood or blood products, vaccines, therapeuticproteins, gene cell therapies, etc. Sponsors submit a BiologicsLicense Application or BLA, requirements of which, includinghuman trials data, are similar to those of the NDA.

FDA’s Center for Devices and Radiological Health (CDRH)regulates firms that manufacture, repackage, re-label, and/orimport medical devices sold in the United States. Most medicaldevices may be marketed only after completing either aPremarket Approval (PMA) or 510(k) application. The excep-tion to this is that certain Class I devices are exempt from the510(k) requirements. A tri-level classification system categorizesdevices according to increasing degree of associated risk fromClass I thru III (Table 2). The PMA applies to products consid-ered to pose the highest level of risk to patients (Class III). Thisprocess is similar in many respects to the BLA or NDA, requir-ing the submission and review of extensive data, includinghuman trials, and culminates in market approval. Products thatrequire a PMA may include, for example, a pacemaker or artifi-cial hip implant. Class I or II products that successfully meet therequirements of a 510(k) application receive “clearance” formarketing.

510(k) ClearanceProducts with 510(k) clearance are relatively well-known amongdermatologists. These range from laser or light-based devices towound dressings that have been used for many years. The rela-tively recent emergence of topical skin creams with 510(k) clear-ance has, however, confounded many clinicians, inspiringincreased interest in understanding the 510(k) clearanceprocess.

First established by FDA more than 30 years ago, device reg-ulations permit a sponsor to pursue 510(k) clearance for Class Ior II devices when the applicant device is “substantially equiva-

• Diagnose• Cure• Mitigate• Treat• Prevent

• Does not achieve primary intended purpose through chemicalaction

• Not dependent on beingmetabolized

• Primary intended useachieved through chemicalaction or, metabolized bythe body

• Diagnose• Cure• Mitigate• Treat• Prevent

Similarities

Table 1. Devices vs. Drugs

DrugsDevices

Differences

lent” to a currently marketed device. A “substantially equiva-lent” device has the same intended use as the predicate andeither the same technological characteristics as the predicate or,if technological characteristics differ, information submitteddoes not raise new questions of safety and effectiveness anddemonstrates that the device is at least as safe and effective asthe predicate.

Until relatively recently, devices that were not substantiallyequivalent to a predicate, even if they met the criteria for ClassI or II status, were designated by the FDA as Class III and hadto pursue a PMA. In the latter part of the last decade, FDAintroduced the “de novo” application status. As a de novoapplicant (the concept has not been widely employed to thispoint), the sponsor must receive a non substantially equiva-lence (NSE) determination for a 510(k) application. The spon-sor can then request de novo classification. If granted the FDAwill review the non-predicated device without requiring theextensive requirements of a PMA. If the FDA determines thatthe original classification of Class III can be changed, thedevice will be re-classified. If not, a PMA would then berequired.

In addition to demonstrating substantial equivalence, the510(k) process requires that the applicant provide data for twokey characteristics of the product. These are 1.) safety or bio-compatibility and 2.) stability. Safety or biocompatibility datahistorically have come mainly from animal studies (includingcontact sensitivity assays, eye irritation assays, etc.) and havebeen used to demonstrate compliance with InternationalStandards Organization criteria (ISO). Proving stability of the

54 Practical Dermatology April 2008

Device Clearance

Information abstracted or adapted from the FDA website (fda.gov)

NDA; New Drug Application: The vehicle through which drug sponsors formally submit to FDA Center for Drug Evaluation and Research to approve a new phar-maceutical for sale and marketing in the US. Data gathered during animal studies and human clinical trials of an Investigational New Drug (IND) become part of theNDA.

ANDA; Abbreviated New Drug Application: Process through which FDA’s Center for Drug Evaluation and Research, Office of Generic Drugs, provides for thereview and ultimate approval of a generic drug product.

BLA; Biologics License Application: Similar to the NDA, it is the process for application to the Center for Biologics Evaluation and Research for approval to mar-ket a biologic agent.

PMA; Premarket Approval Application: Similar to an approved New Drug Application it is an approval granted to the applicant for marketing a particular med-ical device. The application is submitted to the FDA’s Center for Devices and Radiological Health.

510(k): So named because provisions are set forth in Section 510(k) of the FD&C Act, this premarket notification is required of any entity that wants to market inthe US a Class I, II, and III device intended for human use, for which a Premarket Approval (PMA) is not required.

An Abridged Guide to Filing Terms

Class I• Minimal potential for harm / very low risk

• Not to be used in supporting / sustaining life or preventing injury orimpairment

• General controls (registration, listing, cGMPs, labeling)

• Examples: Elastic bandages and exam gloves

Class II• Moderate risk

• Not to be used in supporting / sustaining life or preventing injury orimpairment

• General Controls

• Special controls (special labeling, post-market surveillance and human clin-ical trials)

• Examples: Powered wheelchairs and pregnancy tests

Class III• Pose greatest risk / potential for unreasonable risk of illness or injury

• Intended to be used to support or sustain life or are of substantial impor-tance in preventing impairment of human health

• General and special controls insufficient by themselves to ensure safetyand efficacy

• Examples: Hip implants and pacemakers

Table 2. Device Classification

device through its shelf life typically depended on evidence ofproper protective, sturdy, sealed packaging, etc. In the case oftopical creams, a device applicant would have to demonstrateformulation stability through methods similar to thoserequired for a topical cream drug.

Recently, observers have noted that FDA is requesting clin-ical information that is not strictly required within a 510(k).These data often include human trials data, such as irritationor contact sensitization studies. In some cases, the requestedinformation can resemble the type and scope required for aPMA.

Sponsors of 510(k) cleared products are free to conductpost-approval human clinical trials of their devices. Such trialsare not a strict requirement of the application process.

In addition to establishment of the de novo applicationoption, FDA introduced updates to the quality controls gov-erning the manufacture of medical devices. In fact, currentstandards for devices are arguably more well-defined than fordrugs.

In addition to Good Manufacturing Practices (GMPs) out-lined by the agency, FDA implemented the Quality SystemRegulations (QSR) for devices. The QSR, based on interna-tional quality system requirements, applies broader control tothe entire device development and manufacturing processes toensure a device’s performance by requiring it to be manufac-tured in a reproducible and consistent manner. The QSR intro-duced design controls to the elements of GMP. To be compli-ant with the design control requirements, sponsors must havewritten plans that describe or reference design and develop-ment activities and define responsibilities for implementation.They must also document that they have attempted to identi-fy risks to patients or caregivers related to use or misuse of thedevice and that they have taken steps to minimize those riskswhen possible.

The FDA has the authority to inspect device manufacturers.These inspections are typically pre-announced. FDA inspectsall elements of the QSR. Finally, Medical Device Reporting(MDR) allows FDA to monitor the serious adverse events asso-ciated with the use or misuse of marketed devices. A reportableserious adverse event is one that reasonably suggests that adevice may have caused or contributed to death or seriousinjury.

Devices receive clearance for specific applications, and theymay be marketed only for those approved uses. However, com-panies that wish to receive approval for a new use may submita new 501(k) requesting clearance.

Approval versus Clearance510(k) marketing clearance differs significantly from FDAdrug approval. Approval of an NDA, ANDA, PMA or BLA

signifies that an agent has been proven safe and effective for agiven indication. While devices, like drugs, influence the struc-ture or function of the body, clearance signifies only that thedevice has been shown to be substantially equivalent to a pred-icate device. Though typically not required for 510(k) applica-tion, efficacy data from human trials sometimes are available.

Clinicians should be assured of the consistent quality ofdevices, as FDA has imposed extensive requirements for man-ufacturers/marketers—requirements that are broader in scopefor drug manufacturers/marketers. Though quality require-ments are somewhat different for devices than for drugs, userfees are significantly lower. Whereas basic submission, estab-lishment, and product fees for an NDA can total more than$1.5 million, the fees for a 510(k) submission and establish-ments can be under six thousand dollars.

As with many of the therapeutic and diagnostic productsdermatologists use in practice, one’s opinion of a drug or deviceultimately depends on one’s assessment of the evidence, first-hand experience, and patient experience and satisfaction. ■

April 2008 Practical Dermatology 55

Content of 510(k)Device description

Proposed labeling and instructions for use

Statement of indications for use

Substantial equivalence statement comparing new device to one or morepredicate devices

Supporting data

Summary of safety and effectiveness

Conformance to performance standard(s)

Financial disclosure

Truthful and accurate statement

510(k) Review Process‘K’ number assigned

Initial filing review to determine completeness

Assigned to one reviewer

Reviewed for substantial equivalence to predicate device

Target for review – 90 days

When additional information is requested, review clock stops

FDA Action – SE (substantially equivalent) or NSE (not substantially equiva-lent)

Device ‘cleared’ not ‘approved’

Table 3. 510(k) Application and Review