Premarket Notification Compared With Premarket Approval
One route asks whether a device is enough like something already sold. The other asks whether the device itself is safe and effective. The words cleared and approved are not interchangeable and the difference runs through everything that follows.
The rule in short
Premarket notification under 21 U.S.C. 360(k) asks whether a device is substantially equivalent to a legally marketed predicate, meaning the same intended use and either the same technological characteristics or different ones raising no different questions of safety and effectiveness. Premarket approval under 21 U.S.C. 360e asks whether valid scientific evidence provides reasonable assurance of safety and effectiveness.
Devices reach the market by two principal routes, and confusing them causes trouble in litigation, in procurement and in marketing copy. A cleared device passed a comparison. An approved device passed an evaluation. Both are lawful, both involve substantial work, and they are not the same claim.
What a notification actually asserts
A person who intends to introduce a device into commercial distribution must submit a premarket notification before doing so, unless the device type is exempt. The submission asserts that the device is substantially equivalent to a legally marketed device, called the predicate.
The predicate is the foundation of the whole submission, and choosing one is a strategic decision rather than a clerical one. A predicate with a broad intended use widens what the new device may claim; a predicate with unusual technology narrows the comparison the sponsor has to make. Sponsors may cite more than one predicate where a device combines features, provided the intended use remains the same, and they may not stitch together a use that no single predicate has.
Substantial equivalence has a two-branch definition. The device may have the same intended use as the predicate and the same technological characteristics. Alternatively it may have the same intended use and different technological characteristics, provided the differences do not raise different questions of safety and effectiveness and the information submitted demonstrates that the device is at least as safe and effective as the predicate. The second branch is where most of the work happens, and it is where bench testing, biocompatibility data and, occasionally, clinical data are used to close the gap.
What goes into a notification
Section 807.87 lists the required information: the device name, the establishment registration number, the class and classification regulation, action taken to comply with any applicable performance standard, proposed labels, labeling and advertisements sufficient to describe the device and its intended use, the statement of substantial equivalence, and a comparison with the predicate.
A submission also contains either a summary of the safety and effectiveness information on which equivalence is based, or a statement that the information will be made available on request. The summary route produces a public document, which is why competitors read them. A notification is submitted a stated period before distribution begins, and distribution may not begin until the agency issues its determination.
An order finding a device substantially equivalent means the comparison succeeded. It does not embody an independent conclusion that the device is safe and effective in the sense the approval standard uses, and marketing material that describes a cleared device as approved is inaccurate. The distinction also matters in product liability, where the preemptive effect of federal requirements has been treated very differently for the two routes.
What an approval requires
A premarket approval application must contain complete reports of all information, published or known to the applicant, concerning investigations showing whether the device is safe and effective. It must describe the device's components, properties and principle of operation, the manufacturing methods, facilities and controls, any applicable performance standard, samples where requested, the proposed labeling, and a bibliography of all published reports known to the applicant that concern safety or effectiveness.
The review also proceeds differently. An approval application may be referred to a panel of outside experts, which meets in public, hears from the sponsor and from members of the public, and votes on the questions the agency puts to it. The application file, the sponsor's presentation and the panel's discussion become part of a public record that competitors, plaintiffs and purchasers can read afterward. Nothing comparable happens in a notification, which is reviewed without a public proceeding.
The standard is reasonable assurance of safety and effectiveness supported by valid scientific evidence, which ordinarily means at least one well-designed clinical investigation. The agency may refer the application to an advisory panel for review and recommendation. A manufacturing site inspection is normally conducted before approval, because the description of manufacturing controls is part of what is being approved.
| Feature | Premarket notification | Premarket approval |
|---|---|---|
| Question asked | Is the device substantially equivalent to a predicate? | Is there reasonable assurance of safety and effectiveness? |
| Predicate required | Yes, a legally marketed device | No |
| Evidence typically needed | Comparison data, bench and biocompatibility testing | Valid scientific evidence, usually including clinical investigation |
| Agency output | An order finding the device substantially equivalent or not | An approval order, or a letter identifying deficiencies, or denial |
| Preapproval site inspection | Not ordinarily part of the review | Ordinarily conducted before approval |
| Conditions on marketing | None beyond general and special controls | May restrict sale, distribution and use, and require postapproval studies |
| Route for modifications | A new notification where the change is significant | A supplement, of a type matched to the change |
Conditions, supplements and life after entry
An approval order is not a permission slip that ends the relationship. It may impose conditions of approval: restrictions on sale, distribution or use, postapproval studies with defined protocols and reporting, periodic reports, and specific labeling requirements. Failure to comply with a condition is a ground for withdrawal of approval, which is a materially different exposure from an ordinary compliance problem.
Changes are handled differently by route. For an approved device, a change affecting safety or effectiveness requires a supplement, and the regulation provides several types matched to the significance of the change, including notice-based and real-time mechanisms for narrow categories. For a cleared device, the manufacturer evaluates whether the change could significantly affect safety or effectiveness or represents a major change in intended use, and documents that evaluation whether or not a new notification results. Which route applies is a function of the class, determined as described in device classification and the three classes.
Both routes converge on the same postmarket obligations. Quality system requirements govern how the device is designed and produced, and are examined during the inspections described in manufacturing quality systems and inspections. Reporting duties attach when a device may have caused or contributed to a death or serious injury or has malfunctioned, as set out in adverse event and malfunction reporting. And where a problem in the field requires action, the framework is the one described in recalls, corrections and removals.
Points to carry away
- Notification compares a device with a predicate; approval evaluates the device itself.
- A notification is submitted before introducing a device into commercial distribution.
- A finding of not substantially equivalent places the device in class III.
- Approval requires valid scientific evidence, usually including clinical investigation.
- An approval order may restrict sale, distribution and use and require postapproval studies.
- Modifications are handled by a new notification or by a supplement, depending on the route.
Questions readers ask
Can a device be cleared on the basis of a predicate that was later recalled?
The predicate must be legally marketed, and a device removed from the market for reasons of safety or effectiveness is a problematic choice. Where a predicate has been withdrawn on those grounds, relying on it invites questions about whether the comparison establishes anything useful, and the agency can decline to accept it. Practically, sponsors screen candidate predicates for recall history and for the reasons behind any removal before building a submission around one. Discovering the problem after a submission is filed usually means starting the comparison again.
What does a not substantially equivalent determination actually do?
It places the device in class III by operation of law, because a device that is not within a classified type and not substantially equivalent to a legally marketed device defaults to that class. The sponsor's options are then to submit an approval application, to request de novo classification if the risk profile supports classification into class I or II, or to change the device or its intended use and try the comparison again. A determination is not a finding that the device is unsafe; it is a finding that the comparison route is unavailable.
How are changes to a marketed device handled?
The answer depends on the route the device took to market. For a cleared device, a change or modification that could significantly affect safety or effectiveness, or a major change in intended use, requires a new premarket notification, and the manufacturer must document its analysis when it concludes no new notification is needed. For an approved device, changes affecting safety or effectiveness are made through supplements, which come in several types with different review demands. In both cases the manufacturer's own change control records are what an investigator asks for first.
Sources
- Cornell Legal Information Institute — 21 U.S.C. 360, Registration of Producers of Drugs or DevicesSubsection (k) states the premarket notification requirement.
- Cornell Legal Information Institute — 21 U.S.C. 360e, Premarket ApprovalThe approval standard, the review period, panel referral and the grounds for denial.
- eCFR — 21 CFR 807.81, When a Premarket Notification Submission Is RequiredFirst distribution, significant changes and major changes in intended use.
- eCFR — 21 CFR 807.87, Information Required in a Premarket Notification SubmissionThe contents of a notification, including labeling and the equivalence statement.
- eCFR — 21 CFR 807.100, FDA Action on a Premarket NotificationThe substantial equivalence determination and its consequences.
- eCFR — 21 CFR 814.20, ApplicationThe contents of a premarket approval application, from prior investigations to labeling.
- eCFR — 21 CFR 814.44, Procedures for Review of a PMAPanel review, the possible actions and the conditions an approval order may carry.
Liberty Law Library is a publication, not a law firm. This article states general rules and cites its sources; it is not advice about any particular case, and the law differs by state and changes over time.
More in Drug & Device Regulation
Review Board Oversight and Informed Consent Documents
Under 21 CFR Part 56 a clinical investigation may not begin until an institutional review board has approved it, applying the criteria in 56.111 covering minimized risk, favorable risk-benefit balance, equitable subject selection, informed consent, data monitoring, privacy and safeguards for vulnerable subjects. Part 50 governs consent: 50.20 sets general conditions, 50.25 lists the required elements, and 50.27 requires a signed document.
Labeling: Required Content, Format and Changes
Labeling under 21 U.S.C. 321(m) includes all written, printed or graphic matter on an article, its containers or wrappers, or accompanying it. A product is misbranded under 21 U.S.C. 352 where its labeling is false or misleading in any particular. Prescription labeling follows 21 CFR 201.56 and 201.57, over-the-counter labeling follows 201.66, and changes are made through the supplement categories in 21 CFR 314.70.
Supply Chain Tracing and the Duty to Verify
The drug supply chain provisions at 21 U.S.C. 360eee and following require that transaction information and a transaction statement accompany each change of ownership, that trading partners be authorized, and that product bear an identifier permitting package-level verification. A firm with reason to believe product is counterfeit, diverted, stolen or otherwise unfit must quarantine and investigate it.