Overview
The following describes how the U.S. Food and Drug Administration ("FDA") regulates the pre-marketing process for drugs and medical devices, and the steps that must be taken to obtain FDA authorization to market these products.
Drugs
Under the U.S. Food Drug and Cosmetic Act ("FDCA" or the "Act"), a "new drug" cannot be introduced into interstate commerce unless "approval" of an application for the drug is effective.i In practice, this means that any "new drug" is subject to FDA's New Drug Application ("NDA") requirements. A "new drug" generally includes (i) a drug that is not generally recognized among qualified experts as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof; or (ii) a drug that has become generally recognized as safe and effective in investigations, but that has not been used to a material extent or for a material time under such conditions (other than in investigations).ii It is up to the drug marketer to make the initial determination as to whether the marketer's drug is a "new drug," though FDA possesses the regulatory authority to override the marketer's initial determination. Ultimately, the courts have the final say, though the courts generally have deferred to FDA's determinations.
For a new drug to be approved, the drug sponsor (company, research institution, or other organization that takes responsibility for developing the drug) must show in studies that the drug is "effective" and "safe" for its intended use. With respect to the effectiveness component, the marketer's claims must be supported by "substantial evidence of effectiveness," which requires "adequate and well-controlled clinical investigations."iii While two or more studies are generally needed, the law now permits approval on the basis of a single study in certain cases. With respect to the safety component, risk identification and measurement must be assessed through adequate tests by all methods reasonably applicable, and the results of the tests must show that the drug is safe for use under the conditions prescribed, recommended, or suggested in the proposed labeling.iv
Additionally, for a new drug to be approved, the drug must be adequately labeled and capable of being made consistently with the same identity, strength, and quality as the drugs used in the studies. This means that the labeling cannot be false or misleading, and the chemistry, manufacturing, and controls must be adequate to ensure batch-to-batch consistency with the product tested in the clinical trials.
Chief elements of an NDA include reports of investigations demonstrating safety and effectiveness; identification of drug components and composition; descriptions of methods, facilities, and controls used for drug manufacturing, processing, and packaging; samples (as required); labeling; and patent information. Of note, data gathered during animal studies and human clinical trials of an Investigational New Drug (IND) become an important component of the NDA.
After an NDA is submitted, a team of FDA physicians, statisticians, chemists, pharmacologists, and other scientists typically review the submitter's data and proposed labeling. Note that FDA does not actually perform testing on the drug proposed in the NDA, although FDA may conduct limited research on drug quality, safety, and effectiveness standards. If FDA makes a determination that a drug's health benefits outweigh its known risks, the drug should generally be approved for sale, though there is a possibility that a post-approval study commitment may be a condition of FDA's approval. There is an important period of exclusivity associated with NDAs – up to five years, for a drug consisting of a new chemical entity.
Another route for approval of a new drug is the Abbreviated New Drug Application ("ANDA"). The ANDA process may be appropriate if (i) the conditions of use prescribed, recommended, or suggested in the labeling have been previously approved; (ii) the active ingredients in the drug are the same; (iii) the route of administration, dosage form, and strength are the same; (iv) the product is bioequivalent (i.e., performs in the same manner as the innovator drug); and (v) the labeling is the same. Oftentimes, an ANDA is submitted for FDA's review and ultimate approval of a proposed generic drug product. ANDAs are called "abbreviated" because, since they are based on a preexisting innovator drug, they are typically not required to include preclinical (animal) or clinical (human) data to establish the drug's safety and effectiveness.
If a product is not a "new drug," it can be marketed without FDA approval. Of note, most over-the-counter drugs are not marketed under a NDA or ANDA. However, a drug that is not new is still subject to the FDCA laws prohibiting the introduction into interstate commerce of adulterated or misbranded drugs.v Additionally, the Federal Trade Commission regulates the advertising of these drugs, and requires that their advertising not be false or misleading.
Medical Devices
If a product is labeled, promoted, or used in a manner that is a "device" under the Act, it will be subject to FDA's pre-marketing regulatory controls. Under the Act, a device is: "an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
- recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."vi
FDA categorizes devices into three main classes. Device classification depends on the intended use of the device and also upon indications for use. FDA has explained that for example, a scalpel's intended use is to cut tissue, but that a subset of intended use can arise when a more specialized indication is added in the device's labeling such as, "for making incisions in the cornea." In addition, device classification is risk based, that is, the classification takes into account the risk the device may pose to the device user. The device classes are divided into Class I, Class II, and Class III devices; ranging from devices with the lowest risk (Class I) to those with the proportionately greater risk (Class III).
Class I devices are intended to provide "general controls" sufficient to provide a reasonable assurance of safety and effectiveness. "General controls" may include recall notification and user right to repairs, replacement, or refund. Examples of Class I devices include manual toothbrushes and tongue depressors.
In contrast with Class I devices, for Class II devices, general controls alone are deemed insufficient to provide reasonable assurance of safety and effectiveness. Most Class II devices require "special controls" and FDA clearance through a process known as "510(k) clearance" (named after Section 510(k) of the FDCA, which requires applicable device manufacturers to notify FDA of their intent to market a medical device at least 90 days in advance). "Special controls" might include certain performance standards or post-marketing surveillance. An example of a Class II device would be a laser used for general surgery.
The class of devices that face the strictest level of review by FDA are Class III devices. This is because for Class III devices, general controls and special controls alone are determined to be insufficient to provide reasonable assurance of safety and effectiveness. This classification is applicable to devices that (i) support or sustain human life; (ii) are of substantial importance in preventing impairment of human health; or (iii) are not substantially equivalent to a legally marketed Class I, Class II, or grandfathered (pre-May 28, 1976) Class III device. In general, Class III devices must be "approved" (rather than simply "cleared" through 510(k) clearance) by FDA prior to their marketing. Examples of Class III devices include artificial hearts and lasers for ophthalmic surgery.
As indicated above, with some exceptions, to market a medical device in the United States, a marketer must either (i) submit and obtain clearance of a 510(k) application (applicable to most Class II devices); (ii) submit and obtain approval of a Premarket Approval Application ("PMA") (applicable to most Class III devices); or (iii) submit sections of a PMA via FDA's Product Development Program (an alternative approach for Class II devices and described further below). The device type determines which of the aforementioned three avenues for marketing authorization is appropriate. The vast majority of Class I and some Class II devices are so-called 510(k) exempt and do not require any pre-market submission.
With respect to the 510(k) clearance process, a marketer must demonstrate that the device to be marketed is substantially equivalent to a legally marketed device, though a device cannot be found substantially equivalent to a device that is subject to a PMA.vii A device is substantially equivalent to another device if it has the "same intended use" and either (i) the same technological characteristics; or (ii) different technological characteristics but is as safe and effective as the other devices and does not raise different questions of safety or effectiveness.viii Additionally, a new 510(k) must be filed for a legally marketed device before significantly modifying its design, components, method of manufacture, or intended use. Significant modifications can include changes that could significantly affect the safety or effectiveness of the device or major changes in the intended use of the device. Once the device is determined by FDA to be substantially equivalent to a predicate device, it can then be marketed in the United States.
With some exceptions, PMA approvals are generally required for Class III devices. In contrast with the 510(k) clearance process, PMA approvals require an extensive volume of information and data. FDA regulations provide 180 days for FDA to review the PMA and make a determination.ix However, FDA has admitted that the review time is normally longer. Before approving or denying a PMA, an FDA advisory committee may decide to review the PMA at a public meeting and provide FDA with the committee's recommendation as to whether FDA should approve the submission. After FDA notifies the applicant that the PMA has been approved or denied, a notice is typically posted online (i) announcing the data on which the decision is based, and (ii) providing interested persons an opportunity to petition FDA for reconsideration of the decision.
As an alternative to the PMA process, FDA provides a Product Development Protocol ("PDP"), which combines FDA's Investigational Device Exemption ("IDE") procedures and PMA procedures with a preclinical procedure. The PDP allows a sponsor to come to early agreement with FDA as to what can be done to demonstrate the safety and effectiveness of a new device. Early interaction in the development cycle of a device can permit a sponsor to address concerns of the FDA without wasting time-consuming resources. The key objective here is for FDA and the sponsor to obtain an early agreement on the data and information necessary to approve the device; once agreement is reached, the sponsor is to fulfill the obligations of the PDP to obtain approval.
Conclusion
The Act and FDA practice strongly suggest that members of the pharmaceutical and medical device industry carefully consider how FDA is likely to classify their products that have not yet been introduced into the marketplace. This classification will help inform industry members of required steps toward gaining authorization to market their products in a fashion that promotes compliance and more efficient review by FDA.
Additional Resources
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevice/
https://www.ftc.gov/news-events/media-resources/truth-advertising/health-claims
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