Breaking through confusion to uncover the facts about FDA

Breaking through confusion to uncover the facts about
FDA regulations for various marketed products.
By Joseph Bikowski, MD and Bobbi Drais, MS, RAC
G
enerally speaking, the word “device” almost
always conjures images of a mechanical contraption. Asked just a few years ago to list the
“devices” they use regularly in the clinic, many
dermatologists would have named laser systems,
microdermabrasion machines, UV lightboxes, Unna boots,
punch biopsy instruments, and even hand-held communica-
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tions tools. But when a new generation of topical therapies for
atopic dermatitis emerged with FDA clearance for marketing as
devices, many dermatologists were taken aback.
These agents garnered significant attention for their apparently unusual journey to market, but the reality is that numerous similar topical dressings were already on the market and in
use by dermatologists. Additional similar products are likely to
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April 2008
emerge. To help clinicians understand the meaning of device
clearance, the following review provides a look at current FDA
policies and procedures.
Avenues to Market
Medical products under the purview of the FDA—drugs,
devices, and cosmetics—ultimately reach the US market via several distinct pathways, depending on their classification and
intended use. A drug is essentially any article intended for use in
the diagnosis, cure, mitigation, treatment, or prevention of disease. Drugs encompass any article intended to affect the structure or any function of the body. A drug achieves its primary
intended purposes through chemical action within or on the
body and may be dependent upon being metabolized for the
achievement 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 or
metabolism. A device is any instrument, apparatus, machine,
implant, in vitro reagent, or component part or accessory that is
intended for use in the diagnosis of disease or other conditions,
or in the cure, mitigation, treatment, or prevention of disease. A
device is intended to affect the structure or any function of the
body, but it does not achieve any of its primary intended purposes through chemical action within or on the body and is not
dependent upon being metabolized for the achievement of any
of its primary intended purposes.
FDA oversees two medical product categories that do not
require market “approval”: over-the-counter (OTC) drugs and
cosmetics. Note that unlike drugs and devices, cosmetics do not
alter the structure or function of the body. Their intended use is
for cleansing, beautifying, promoting attractiveness or altering
appearance. Over-the-counter drugs must adhere to an OTC
monograph, which outlines requirements for labeling and testing of these agents. The same general manufacturing principals
that guide NDA and ANDA products guide the production of
OTC drugs.
Drugs reach the market upon approval of a new drug application (NDA) or, in the case of generic equivalents for approved
drugs, an abbreviated new drug application (ANDA). This
process applies to any new chemical entity, formulation, or indication. As part of the review and approval process, the agency
acquires and reviews information and data from the application
sponsor, including but not limited to data from clinical trials in
humans. Most dermatologists are quite familiar with the
numerous components of this costly and lengthy process.
Similar to the drug approval process, the biologics licensing
process applies to any biologically-based therapeutic agent,
whether it be blood or blood products, vaccines, therapeutic
proteins, gene cell therapies, etc. Sponsors submit a Biologics
License Application or BLA, requirements of which, including
human trials data, are similar to those of the NDA.
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FDA’s Center for Devices and Radiological Health (CDRH)
regulates firms that manufacture, repackage, re-label, and/or
import medical devices sold in the United States. Most medical
devices may be marketed only after completing either a
Premarket Approval (PMA) or 510(k) application. The exception to this is that certain Class I devices are exempt from the
510(k) requirements. A tri-level classification system categorizes
devices according to increasing degree of associated risk from
Class I thru III (Table 2). The PMA applies to products considered to pose the highest level of risk to patients (Class III). This
process is similar in many respects to the BLA or NDA, requiring the submission and review of extensive data, including
human trials, and culminates in market approval. Products that
require a PMA may include, for example, a pacemaker or artificial hip implant. Class I or II products that successfully meet the
requirements of a 510(k) application receive “clearance” for
marketing.
510(k) Clearance
Products with 510(k) clearance are relatively well-known among
dermatologists. These range from laser or light-based devices to
wound dressings that have been used for many years. The relatively recent emergence of topical skin creams with 510(k) clearance has, however, confounded many clinicians, inspiring
increased interest in understanding the 510(k) clearance
process.
First established by FDA more than 30 years ago, device regulations permit a sponsor to pursue 510(k) clearance for Class I
or II devices when the applicant device is “substantially equiva-
Table 1. Devices vs. Drugs
Devices
Drugs
Similarities
• Diagnose
• Cure
• Mitigate
• Treat
• Prevent
• Diagnose
• Cure
• Mitigate
• Treat
• Prevent
Differences
• Does not achieve
primary intended
purpose through chemical
action
• Primary intended use
achieved through chemical
action or, metabolized by
the body
• Not dependent on being
metabolized
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Device Clearance
An Abridged Guide to Filing Terms
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 pharmaceutical 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 the
NDA.
ANDA; Abbreviated New Drug Application: Process through which FDA’s Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the
review 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 market 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 medical 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 in
the US a Class I, II, and III device intended for human use, for which a Premarket Approval (PMA) is not required.
lent” to a currently marketed device. A “substantially equivalent” device has the same intended use as the predicate and
either the same technological characteristics as the predicate or,
if technological characteristics differ, information submitted
does not raise new questions of safety and effectiveness and
demonstrates that the device is at least as safe and effective as
the predicate.
Until relatively recently, devices that were not substantially
equivalent to a predicate, even if they met the criteria for Class
I or II status, were designated by the FDA as Class III and had
to pursue a PMA. In the latter part of the last decade, FDA
introduced the “de novo” application status. As a de novo
applicant (the concept has not been widely employed to this
point), the sponsor must receive a non substantially equivalence (NSE) determination for a 510(k) application. The sponsor can then request de novo classification. If granted the FDA
will review the non-predicated device without requiring the
extensive requirements of a PMA. If the FDA determines that
the original classification of Class III can be changed, the
device will be re-classified. If not, a PMA would then be
required.
In addition to demonstrating substantial equivalence, the
510(k) process requires that the applicant provide data for two
key characteristics of the product. These are 1.) safety or biocompatibility and 2.) stability. Safety or biocompatibility data
historically have come mainly from animal studies (including
contact sensitivity assays, eye irritation assays, etc.) and have
been used to demonstrate compliance with International
Standards Organization criteria (ISO). Proving stability of the
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Table 2. Device Classification
Class I
• Minimal potential for harm / very low risk
• Not to be used in supporting / sustaining life or preventing injury or
impairment
• 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 or
impairment
• General Controls
• Special controls (special labeling, post-market surveillance and human clinical 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 importance in preventing impairment of human health
• General and special controls insufficient by themselves to ensure safety
and efficacy
• Examples: Hip implants and pacemakers
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device through its shelf life typically depended on evidence of
proper protective, sturdy, sealed packaging, etc. In the case of
topical creams, a device applicant would have to demonstrate
formulation stability through methods similar to those
required for a topical cream drug.
Recently, observers have noted that FDA is requesting clinical information that is not strictly required within a 510(k).
These data often include human trials data, such as irritation
or contact sensitization studies. In some cases, the requested
information can resemble the type and scope required for a
PMA.
Sponsors of 510(k) cleared products are free to conduct
post-approval human clinical trials of their devices. Such trials
are not a strict requirement of the application process.
In addition to establishment of the de novo application
option, FDA introduced updates to the quality controls governing the manufacture of medical devices. In fact, current
standards for devices are arguably more well-defined than for
drugs.
In addition to Good Manufacturing Practices (GMPs) outlined by the agency, FDA implemented the Quality System
Regulations (QSR) for devices. The QSR, based on international quality system requirements, applies broader control to
the entire device development and manufacturing processes to
ensure a device’s performance by requiring it to be manufactured in a reproducible and consistent manner. The QSR introduced design controls to the elements of GMP. To be compliant with the design control requirements, sponsors must have
written plans that describe or reference design and development activities and define responsibilities for implementation.
They must also document that they have attempted to identify risks to patients or caregivers related to use or misuse of the
device and that they have taken steps to minimize those risks
when possible.
The FDA has the authority to inspect device manufacturers.
These inspections are typically pre-announced. FDA inspects
all elements of the QSR. Finally, Medical Device Reporting
(MDR) allows FDA to monitor the serious adverse events associated with the use or misuse of marketed devices. A reportable
serious adverse event is one that reasonably suggests that a
device may have caused or contributed to death or serious
injury.
Devices receive clearance for specific applications, and they
may be marketed only for those approved uses. However, companies that wish to receive approval for a new use may submit
a new 501(k) requesting clearance.
Approval versus Clearance
510(k) marketing clearance differs significantly from FDA
drug approval. Approval of an NDA, ANDA, PMA or BLA
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Table 3.
510(k) Application and Review
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 more
predicate 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 equivalent)
Device ‘cleared’ not ‘approved’
signifies that an agent has been proven safe and effective for a
given indication. While devices, like drugs, influence the structure or function of the body, clearance signifies only that the
device has been shown to be substantially equivalent to a predicate device. Though typically not required for 510(k) application, efficacy data from human trials sometimes are available.
Clinicians should be assured of the consistent quality of
devices, as FDA has imposed extensive requirements for manufacturers/marketers—requirements that are broader in scope
for drug manufacturers/marketers. Though quality requirements are somewhat different for devices than for drugs, user
fees are significantly lower. Whereas basic submission, establishment, and product fees for an NDA can total more than
$1.5 million, the fees for a 510(k) submission and establishments can be under six thousand dollars.
As with many of the therapeutic and diagnostic products
dermatologists use in practice, one’s opinion of a drug or device
ultimately depends on one’s assessment of the evidence, firsthand experience, and patient experience and satisfaction. ■
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