Q&A: marketing authorisation for pharmaceuticals and medical devices in USA

Marketing authorisation

Time frame

How long does it take, in general, to obtain an authorisation from application to grant, what fees are payable and what is the normal period of validity of the authorisation?

The review period for pre-market applications for drugs and devices depends upon the commitments made by the Food and Drug Administration (FDA) pursuant to four user fee statutes:

These statutes are reauthorised by Congress every five years, with associated FDA performance commitments. The FDA is authorised under these statutes to collect user fees from drugs, biologics and device companies. Under PDUFA, new drug applicants must pay an application fee and a programme fee. Under MDUFA, device applicants must pay an application fee and an establishment registration fee. Under GDUFA, generic drug applicants must pay an application fee and a programme fee. GDUFA also levies fees for certain drug master file owners and certain types of facilities (active pharmaceutical ingredient facilities, finished dosage form facilities and contract manufacturing facilities). Under BsUFA, biologics applicants must pay an application fee, a product development fee and a programme fee.

The target review periods and fees for applications vary by year and type of product. For instance, for standard drug applications, the FDA’s current goal is to review 90 per cent of applications within 10 months of the 60-day filing date and 90 per cent of priority review applications (for serious conditions for which there is an unmet need) within six months of the 60-day filing date. For medical devices, the FDA’s current goal is to reach a decision on pre-market notifications made under section 510(k) of the Food, Drug, and Cosmetic Act (FDCA) within 108 days and within 290 days for pre-market approval applications.

There is no expiration date for FDA marketing authorisations issued for drugs (new drug or abbreviated new drug applications), biologics (biologics licence applications) or medical devices (pre-market approval, 510(k) or de novo), but all regulated medical products may be removed from the market by the FDA for cause or may be withdrawn voluntarily by the sponsor.

Protecting research data

What protections or exclusivities apply to the data submitted by originators to gain initial approval and, on variation or new application, to add indications or pharmaceutical forms?

In general, the FDA will not disclose the existence of an application or abbreviated application unless this has previously been publicly disclosed or acknowledged by the company. However, once a drug application or supplement has been approved, the FDA is allowed to disclose certain ‘safety and effectiveness data’ to the public. Safety and effectiveness data, as defined in Title 21, section 314.430(a) of the Code of Federal Regulations (CFR), refers to all animal and clinical studies, and tests of the drug for identity, stability, purity, potency and bioavailability. The regulations under Title 21, sections 312.130 and 312.340 of the CFR set forth the specific parameters within which the FDA may disclose data and information in an investigational new drug application, a new drug application or an abbreviated new drug application.

Freedom of information

To what extent and when can third parties make freedom of information applications for copies of research data submitted by applicants for authorisation to market medicinal products or medical devices?

The Freedom of Information Act (FOIA), which was enacted in 1966, is a disclosure statute that requires federal agencies to disclose information requested by the public unless the information falls under a specific exemption. The FDA’s FOIA regulations are set forth in Title 21, Part 20 of the CFR.

While any person can submit a FOIA request to the FDA for non-public information or data, the FDA is prohibited from disclosing trade secrets or commercial or financial information that is privileged or confidential. The FDA will typically redact such information with input from the sponsor. Nonetheless, significant information regarding approved applications and FDA reviews may be obtained through the FOIA. For investigational products, the FDA will not acknowledge the existence of an investigational new drug application pursuant to Title 21, section 312.130 of the CFR or an investigational device exemption pursuant to Title 21, section 812.38 of the CFR if the applicant has not made the information public. Information in such submissions is generally not available for public release.

Regulation of specific medicinal products

What are the specific requirements and processes for marketing approval of the major categories of regulated products?

Companies seeking to market and sell prescription drugs, medical devices, and biologicals and biosimilars in the United State must obtain FDA approval (or, in the case of certain devices, clearance) before such products can enter commercial distribution. There are certain low-risk devices that are, by regulation, exempt from having to submit a pre-market notification to the FDA. Other categories of regulated products, such as dietary supplements and cosmetics, generally are not required to obtain FDA approval before entering the market.

For new drugs, sponsors are required to submit a new drug application under section 505(b) of the FDCA. For generic drugs, sponsors are required to submit an abbreviated new drug application under section 505(j) of the FDCA.

New biological products, as well as biosimilars and interchangeable biological products, must be licensed by way of the submission of a biologics licence application pursuant to the Public Health Service Act as amended by the Biologics Price Competition and Innovation Act of 2009.

For medical devices, the FDA classifies products based on risk level: Class I (lowest risk), Class II (moderate risk) and Class III (highest risk). Class I devices and a few Class II devices are generally exempt from pre-market notification requirements under section 510(k) of the FDCA. For most Class II devices, the applicant must submit a 510(k) pre-market notification application to demonstrate that the device is ‘substantially equivalent’ to another commercially marketed device (ie, the predicate device) to obtain clearance from the FDA. For Class III devices, the applicant must file a pre-market approval application, and demonstrate with sufficient data that the device is safe and effective for its intended use. In the case of novel lower-risk devices where there is no predicate device available, the default is a Class III classification. However, a sponsor can also request a de novo classification into Class I or Class II.

Outside of the above categories, products such as dietary supplements and cosmetics are generally not required to obtain FDA approval prior to marketing in the United States. However, if a dietary supplement or cosmetic is marketed as having an intended use that meets the definition of a drug or device, then the product may be deemed an unapproved new medical product subject to FDA approval.

Homeopathic products are drugs that contain active ingredients that are listed in the Homeopathic Pharmacopoeia of the United States. The FDA has not approved any homeopathic drugs to date. Importantly, homeopathic products are not exempt from the regulatory requirements that apply to drugs and, therefore, the regulatory status of such products is not certain. In October 2019, the FDA issued draft guidance indicating that the agency is taking a risk-based enforcement approach to homeopathic drugs.

Post-marketing surveillance of safety

What pharmacovigilance or device vigilance obligations apply to the holder of a relevant authorisation once the product is placed on the market?

Companies are required to report adverse events involving pharmaceutical drugs (Title 21, section 314.80 of the CFR), biologic products (Title 21, section 600.80 of the CFR) and medical devices (Title 21, section 803 of the CFR). Drug sponsors must submit domestic and foreign adverse events that are both serious and unexpected as soon as possible, but no later than 15 working days. Drug sponsors must also submit periodic reports with aggregated safety information on a quarterly basis for the first three years post-approval and annually thereafter.

The Medical Device Reporting Regulation (Title 21, Part 803 of the CFR) imposes mandatory requirements on manufacturers, importers and device user facilities to report certain device-related adverse events and product problems to the FDA. The specific obligations under this regulation vary depending on the company’s role. Manufacturers are required to report deaths, serious injuries and malfunctions to the FDA within 30 days of becoming aware of an event. If the event requires remedial action to prevent an unreasonable risk of substantial harm to the public, manufacturers must report the event to the FDA within five days. Importers must report deaths and serious injuries to the FDA and the manufacturer within 30 days of becoming aware of the event. In addition, importers must report malfunctions only to the manufacturer within 30 days of becoming aware of the event.

Device user facilities (ie, hospitals, ambulatory surgical facilities, nursing homes, outpatient diagnostic facilities or outpatient treatment facilities) must report any suspected medical device-related deaths to both the FDA and the manufacturer within 10 days of becoming aware. Device user facilities must report device-related serious injuries to the manufacturer within 10 days of becoming aware or to the FDA if the medical device manufacturer is unknown.

Other authorisations

What authorisations are required to manufacture, import, export or conduct wholesale distribution and storage of medicinal products and medical devices? What type of information needs to be provided to the authorities with an application, what are the fees, and what is the normal period of validity?

By regulation, under Title 21, Part 207 of the CFR, the FDA requires domestic facilities engaged in the manufacture of drugs or devices, or both, to complete establishment registration and listing. Certain foreign facilities must also complete FDA establishment registration and listing. Whether a particular facility must register with the FDA and list products depends on the specific activities being performed at the facility. Generally, a wholesale distributor that does not engage in manufacturing or import activities is not required to register with the FDA, but every wholesale distributor of prescription drugs must be licensed by the applicable state licensing authority under Title 21, section 205.4 of the CFR.

At the state level, each of the 50 states and the District of Columbia have a board of pharmacy or local department of health, which may require certain in-state and out-of-state facilities to be licensed or registered. Each state has its own laws and regulations regarding the type of products and activities that it regulates. If a state permit or licence is required, the state board of pharmacy (or similar agency) may require the entity to provide various information regarding the company and products, pay a filing fee, undergo a facility inspection or post a bond. As a condition for state licensure, some states also require independent certification (eg, verified-accredited wholesale distributors) to engage in the wholesale distribution of drugs.

Sanctions

What civil, administrative or criminal sanctions can authorities impose on entities or their directors and officers for breach of the requirements concerning controlled activities?

Violations of the FDCA can result in civil or criminal enforcement actions, monetary penalties and imprisonment (for criminal violations). The FDA, through the Department of Justice, may seek a court injunction to prevent further violations, or to detain or seize certain violative products in commerce. The FDA also has the authority to debar individuals or companies from working in the industry and can disqualify clinical investigators who have violated applicable FDA regulations. Conduct that violates the FDCA may also give rise to the violation of other federal laws such as the False Claims Act, which penalises individuals and companies that attempt to defraud the government. Courts in the United States have reached different conclusions on whether FDCA violations may provide a basis for liability under the False Claims Act.

Exemptions

What, if any, manufacture and supply of medicinal products is exempt from the requirement to obtain an approval to market?

For most over-the-counter (OTC) drugs (eg, hand sanitisers, sunscreen products, cough-cold relief medicines), the FDA does not require pre-market approval. However, such OTC drugs must be formulated and labelled in accordance with the conditions set forth in the appropriate OTC monograph. They must also comply with regulatory requirements, such as drug establishment and registration, and comply with good manufacturing practices.

OTC monographs establish permitted conditions for OTC drugs, such as active ingredients, indications, doses, routes of administration, labelling and testing. Products that do not meet OTC monographs are deemed new drugs and are subject to the full new drug application process. The 2020 enactment of the Over-the-Counter Monograph Safety, Innovation, and Reform Act has recently streamlined processes for issuing, revising and amending OTC monographs.

Under the Compounding Quality Act of 2013, certain medicinal products may be compounded by pharmacies on a per-patient basis under section 503A of the FDCA or produced at ‘outsourcing facilities’ under section 503B of the FDCA without FDA pre-market approval. Outsourcing facilities are FDA-registered entities that are engaged in the compounding of sterile drugs. State boards of pharmacy have primary responsibility for overseeing state-licensed pharmacies, which must comply with state standards, whereas the FDA conducts inspections of FDA-registered outsourcing facilities, which must comply with current good manufacturing practices.

Parallel trade

Are imports allowed into your jurisdiction of finished products already authorised in another jurisdiction, without the importer having to provide the full particulars normally required to obtain an authorisation to market? What are the requirements?

Under current US law, finished drugs must first receive FDA approval to be imported into the United States unless they are subject to a narrow personal use exemption. Similarly, finished medical devices cannot be imported into the United States if they do not have the requisite clearance under section 510(k) of the FDCA, pre-market approval or exemption. However, device parts, sub-assemblies and components may be imported into the United States under certain circumstances, such as for further manufacturing or repairs.