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• potential FDA audits of the nonclinical study and clinical trial sites that generated the data in support of the BLA; and
• FDA review and approval of the BLA.
Post-Approval Requirements for Biologics in the United States
Once a BLA is approved, a product is subject to certain post-approval requirements. For instance, the FDA closely regulates the post-
approval marketing and promotion of biologics, including standards and regulations, off-label promotion, industry-sponsored scientific
and educational activities and promotional activities involving the internet. Biologics may be marketed only for the approved
indications and in accordance with the provisions of the approved labeling. Adverse event reporting and submission of periodic reports
is required following the FDA approval of a BLA. The FDA also may require post-marketing testing, known as Phase IV testing, Risk
Evaluation and Mitigation Strategies, or REMS, and surveillance to monitor the effects of an approved product or place conditions on
an approval that could restrict the distribution or use of the product. In addition, quality control as well as product manufacturing,
packaging and labeling procedures must continue to conform to cGMP after approval. Manufacturers and certain of their subcontractors
are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced
inspections by the FDA during which the agency inspects manufacturing facilities to assess compliance with applicable regulations
such as cGMP and the Quality System Regulation. Accordingly, manufacturers must continue to expend time, money and effort in the
areas of production and quality control to maintain compliance with cGMP. Regulatory authorities may withdraw product approvals or
request product recalls if a company fails to comply with regulatory standards, if it encounters problems following initial marketing, or
if previously unrecognized problems are subsequently discovered.
U.S. Medical Device Regulation
The FDA regulates the sale and distribution in interstate commerce of medical devices under FFDCA. Devices must undergo premarket
review by the FDA prior to commercialization unless the device is of a type exempted from such review by statute, regulation, or
pursuant to the FDA’s exercise of enforcement discretion. Pursuant to the FFDCA, medical devices are subject to varying degrees of
regulatory control and are classified in one of three classes depending on the controls the FDA determines necessary to reasonably
ensure their safety and effectiveness.
Class I devices are those for which reasonable assurance of safety and effectiveness can be provided by adherence to the FDA’s general
controls for medical devices, which include applicable portions of the FDA’s Quality System Regulation, or QSR, facility registration
and product listing, reporting of adverse medical events and appropriate, truthful and non-misleading labeling, advertising and
promotional materials. Many Class I devices are exempt from premarket regulation; however, some Class I devices require premarket
clearance by the FDA through the 510(k) premarket notification process described below.
Class II devices are subject to the FDA’s general controls, and any other special controls, such as performance standards, post-market
surveillance, and the FDA guidelines, deemed necessary by the FDA to provide reasonable assurance of the devices’ safety and
effectiveness. Premarket review and clearance by the FDA for Class II devices are accomplished through the 510(k) premarket
notification procedure, although some Class II devices are exempt from the 510(k) requirements. Premarket notifications are subject to
user fees, unless a specific exemption applies. To obtain 510(k) clearance, a manufacturer must submit a premarket notification
demonstrating that the proposed device is “substantially equivalent” to a predicate device, which is a previously cleared 510(k) device
or a pre-amendment device that was in commercial distribution before May 28, 1976, for which the FDA has not yet called for the
submission of a PMA application. In determining substantial equivalence, the FDA assesses whether the proposed device has the same
intended use as the predicate device, and the same technological characteristics as the predicate device or different technological
characteristics but the information submitted in the premarket notification demonstrates the device is as safe and effective as a legally
marketed device and does not raise different questions of safety and effectiveness than the predicate device. The FDA may request
additional information, including clinical data. Under the FFDCA, a manufacturer submits a premarket notification 90 days before
introducing a device into interstate commerce, but the FDA’s review of the premarket notification can take significantly longer. If the
FDA determines that the device is substantially equivalent to the predicate device(s), the subject device may be marketed. However, if
the FDA makes a not substantially equivalent determination, then the device would be regulated as a Class III device, discussed below.
If a manufacturer obtains a 510(k) clearance for its device and then makes a modification that could significantly affect the device’s
safety or effectiveness, a new premarket notification must be submitted to the FDA.
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