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 drugs and devices depends upon the commitments made by the Food and Drug Administration (FDA) as part of the enactment of user fee statutes. Currently, the target performance is the review of 90 per cent of standard drug applications within 10 months of a 60-day filing period, and for priority review applications (for serious conditions for which there is an unmet need), six months after the filing period. For device 510(k)s, the current typical review time is 120 days, and 315 days for premarket approval (PMA). Fees for applications vary by year, and type of product, and are governed by user fee statutes, which are reauthorised by Congress every five years, with associated FDA performance commitments. There is no limit on the validity of an authorisation, although applications may be withdrawn by the FDA under certain scenarios of non-compliance.

Protecting research data

What protection 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 addition to patent protections, there are various statutory exclusivity periods available, including:

  • five years of data exclusivity for the first approval of a drug that is a new chemical entity under a new drug application (NDA);
  • 12 years of exclusivity for the first approval of a biological new molecular entity under a biologics licence application;
  • three years of additional exclusivity for supplemental NDAs (eg, for new indications or dosage forms) for which one or more clinical studies conducted by the applicant and are essential to the approval;
  • seven years of marketing exclusivity for the approval of a designated orphan drug to treat the designated rare disease or disorder;
  • six months of add-on data exclusivity for fulfilling an FDA written request for the conduct of a paediatric study; and
  • five years of additional data exclusivity for the approval of a specially designated antibiotic product.

 

Other incentives, known as priority review vouchers, which permit a more rapid FDA review of products not otherwise eligible for such review, may also be granted if a company obtains designation and achieves approval of a product for a rare paediatric disease, material threat countermeasure or neglected tropical disease. Such vouchers are transferable under certain conditions.

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?

Any party may submit a request for such data under the Freedom of Information Act (FOIA), but FDA regulations and exceptions under the FOIA for trade secret information limit the release of certain proprietary data. Nonetheless, significant information regarding approved applications and FDA reviews may be obtained via the FOIA. For investigational products, the FDA will not acknowledge the existence of an investigational new drug or an investigational device exemption if the applicant has not made the information public, and information in such submissions is generally not available for public release.

Regulation of specific medicinal products

Are there specific rules for approval, and rewards or incentives for approval, of particular types of medicinal products, such as traditional herbal and homeopathic products, biologicals and biosimilars, controlled drugs, orphan drugs and those for paediatric use?

Herbal products that only bear claims relating to an impact on bodily structure or function and contain permitted ingredients may be marketed as dietary supplements without FDA approval. New ingredients used in such products must be the subject of an FDA clearance. However, herbal products with disease or disorder claims are generally subject to the same process for drug approval as purified chemical drugs, with adaptations for the botanical nature of the product.

Homeopathic drugs are permitted under the Federal Food, Drug, and Cosmetic Act (FDCA), but must be marketed in a manner consistent with the Homeopathic Pharmacopoeia and the traditional formulation and labelling constraints for such products.

Biological products are regulated under both the Public Health Service Act and the FDCA, and the process is largely the same as the process for review of NDAs. Biosimilars and interchangeable biological products are licensed under the Public Health Service Act as amended by the Biologics Price Competition and Innovation Act. Such products must demonstrate that they are highly similar or interchangeable with a reference licensed biological product. To date, only one interchangeable biological product has been licensed by the FDA. 

Innovator biologic products receive 12 years of data exclusivity, and four years from approval before a biosimilar application may be filed. The first licensed interchangeable biologic receives one year of marketing exclusivity vis-à-vis other interchangeable products that may be licensed.

Orphan drugs are approved in the same manner as other drug and biological products, although they must be designated as an orphan product prior to application submission, and must be approved for the rare disease for which designation was obtained. Similarly, paediatric drugs are approved through normal processes, although additional data on the paediatric population may be required. Orphan drugs may receive seven years of market exclusivity if approved for the designated orphan indication.

Controlled substances are also approved under the general new drug application (NDA) processes; however, such substances are subject to a scheduling recommendation by the FDA and a scheduling determination via notice and comment rule-making by the Drug Enforcement Administration, which may delay product approval, subject to certain statutory constraints.

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?

Post-marketing safety reporting requirements for human marketed drug and biological products are found at Chapter 21 of the Code of Federal Regulations (21 CFR) sections 310.305, 314.80, 314.98, 600.80 and 600.81. Such regulations require that post-marketing safety reports be submitted to the FDA for serious and unexpected adverse experiences from all sources (domestic and foreign), and for spontaneously reported adverse experiences that occur domestically and that are serious and expected, non-serious and unexpected, and non-serious and expected.

The Medical Device Reporting Regulation at 21 CFR Part 803 imposes mandatory requirements for manufacturers, importers and device user facilities to report certain device-related adverse events and product problems to the FDA. Manufacturers are required to report to the FDA when they learn that any of their devices may have caused or contributed to a death or serious injury, and must also report to the FDA when they become aware that their device has malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. Importers are required to report to the FDA and the manufacturer when they learn that one of their devices may have caused or contributed to a death or serious injury. The importer must report only to the manufacturer if their imported devices have malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur. In addition, ‘device user facilities’ (ie, hospitals, ambulatory surgical facilities, nursing homes, outpatient diagnostic facilities or outpatient treatment facilities (that are not a physician’s office)) must report a suspected medical device-related death to both the FDA and the manufacturer, and a medical device-related serious injury to the manufacturer, 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?

Various requirements apply. Drug, biologicals and device manufacturers must register their establishments with the FDA and list the products associated with each facility.

Application fees for NDAs and BLAs are currently over US$2.5 million and a PMA for a device is subject to a fee in the range of US$320,000. Establishment and programme fees may apply to certain classes of products, and certain exceptions also may apply.

The content of applications varies depending on the type of product, but, in general, applications for approval contain extensive information on the content and manufacturing of the product, as well as all of the various in vitro, animal and clinical data developed to support a finding of safety and effectiveness or other regulatory standard. For drug products, an NDA submission also includes the listing of patents, which may be the subject of certification by applicant for the generic and abbreviated new drug application and subsequent litigation with the reference listed drug application holder.

Drug and device distributors may be subject to state licence or permit requirements, which typically require providing various information regarding the company and products, paying a relatively small fee, and, in some cases, posting a bond.

Although the Department of Health and Human Services is pursuing plans to allow broader importation of products, at present drugs generally can only be imported into the United States by the manufacturer. Manufacturers and those in the drug distribution chain must also comply with drug track and trace requirements, which mandate the passing of a pedigree and investigation of reports of suspect or illegitimate products.

In general, applications remain in effect and are subject to fees and other requirements until discontinued or withdrawn by the manufacturer, or withdrawn by the FDA via a formal process, which is rarely undertaken by the agency.

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 misdemeanour and felony convictions and imprisonment, as well as fines; civil penalties are also available for certain violations. The FDA also has authority, working with the Department of Justice, to seek a court injunction to prevent further violations, or to detain or seize certain products in commerce. Those committing fraud in the drug application process may be subject to debarment from working with companies submitting applications to the FDA. In addition, other laws governing the submission of claims for government payment for biomedical products, such as the False Claims Act, may result in both huge civil settlements and the imposition of corporate integrity agreements by the Department of Health and Human Services Office of Inspector General, and exclusion from government healthcare programmes.

Exemptions

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

Certain over-the-counter (OTC) drug products may be marketed without FDA approval if they comply with FDA regulations, known as ‘OTC monographs’, that provide permitted active ingredients, indications and instructions for use, as well as current good manufacturing practice (cGMP) requirements. Products that do not fall within OTC monographs may be deemed OTC via the full NDA or NDA supplement process. The 2020 enactment of the Over-the-Counter Monograph Safety, Innovation, and Reform Act has recently streamlined processes for seeking changes to existing monographs.

Under the Compounding Quality Act, certain medicinal products may be compounded by pharmacies on a per-patient basis or produced in outsourcing facilities for more general use, without FDA approval. Such parties must comply with pharmacy compounding or cGMPs, respectively, and otherwise stay within the boundaries for such products. For example, such pharmacies and outsourcing facilities may not produce products that are essentially the same as commercially available approved drug products.

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, drug and biological products may be imported into the United States solely by the application holder for the approved product. Medical devices may be imported if compliant with any required 510(k), PMA or exemption.