FDA Requirements - Authority - Acts

Biologics Control Act (also known as the Virus-Toxin Act)

1902 Biologics The act authorized the Hygienic Laboratory of the Public Health and Marine Hospital Service (which eventually became PHS) to issue regulations governing all aspects of commercial production of vaccines, serums, toxins, antitoxin and similar products with the objective of ensuring their safety, purity and potency.

Pure Food and Drugs Act

1906 aka Wiley Act (Dr. Harvey Wiley) Prohibited "misbranding and adulteration" Devices: All US medical device regulations are codified under 21 CFR Parts 800-899. The modernization of the Pure Food and Drugs Act was driven, in part, by the recognized need to introduce a definition of medical devices into federal law. Drugs: This act was the true beginning of federal food and druglegislation intended to protect Americans from harmful substances and the deceptive practices that were becoming more and more common.

Federal Food, Drug, and Cosmetic Act

1938 FD&C Products must be shown to be "safe;" authorized factory inspections Devices: the first law to mandate requirements for exporting unapproved devices. Drugs Biologics

Public Health Service Act

1944 Biologics Required Product License Application/Establishment License Application (PLA/ELA, precursor to the BLA); gave seizure power The Public Health Service Act of 1944 (PHS Act) saw the reorganization of PHS, with authority given to NIH to license, research and develop new biological products. • Hence, one of the primary historical differences between biologics and drugs has been the inherent government research component of biologics as opposed to the testing and regulation emphasis for drugs. • In addition, because biologics are derived from living organisms, immunogenicity issues and how they are addressed in nonclinical and clinical studies often distinguish them from small-molecule drugs.

Durham-Humphrey Amendment

1951 Drugs • clarified what constituted a prescription versus an over-the-counter drug.

Factory Inspection Amendment

1953 • Legal foundation for FDA Form 483 and Form 484 • Removed need for FDA to obtain consent before performing inspection

Kefauver-Harris Drug Amendments

1962 Drugs • mandated the establishment of efficacy as well as safety before a drug could be marketed • required FDA to assess the efficacy of all drugs introduced since 1938, instituted stricter agency control over drug trials (including a requirement that patients involved must give their informed consent), • transferred regulation of prescription drug advertising from FTC to FDA • established Good Manufacturing Practice (GMP) requirements for the drug industry • granted FDA greater powers to access company production and control records to verify those practices.

Fair Packaging and Labeling Act

1966 Devices Drugs

Drug Listing Act

1972 • Manufacturing establishment registration (manufacture, preparation, propagation, compounding, or processing) • Drug listing; list of drugs introduced or discontinued to be submitted semi-annually

Medical Device Amendments

1976: Ensured medical device safety and effectiveness Three risk-based classes • I (least) to III (highest) • Different levels of regulatory scrutiny Requirements for establishment registration and device listing established the ground rules and standards to which all US medical device manufacturers and importers must now adhere: the Medical Device Amendments to the FD&C Act. The new law applied safety and effectiveness safeguards to new devices and required FDA to establish, for the first time: regulations concerning establishment registration and device listing; Good Manufacturing Practices (GMPs) for medical devices; medical device reporting (MDR); and guidelines on policy, procedures and industry responsibilities for field corrections and removals. established three classes of medical devices, each requiring a different level of regulatory scrutiny, up to premarket approval. The three classes were based on the degree of control necessary to assure that the devices were safe and effective. The amendments also made provisions for device listing, establishment registration and adherence to GMPs. 1992: • Clarified device tracking, post-market surveillance, device reporting, and repair, replacement or refund provision The primary impact of the 1992 Medical Device Amendments was to clarify certain terms and to establish a single reporting standard for device user facilities, manufacturers, importers and distributors. • introduction of the Humanitarian Device Exemption (HDE), the medical device equivalent of orphan drug designation, providing limited exemptions from the law for devices intended to treat or diagnose rare diseases or conditions affecting fewer than 4,000 persons • promulgation of the Quality System Regulation, resulting in substantial revisions that essentially harmonized US GMPs for medical devices with the European quality system regulations in EN 46001 and ISO 9001,1 and added design controls to the GMP regulation, bringing product development under FDA scrutiny for the first time • establishment of a regulatory requirement (previously an FDA request) that manufacturers and distributors promptly report field corrections and removals to FDA within 10 days after their initiation • promulgation of the first device tracking regulation

Orphan Drug Act

1983 Drugs The Orphan Drug Act of 1982 (ODA) was signed into law (Public Law 97-414)1 on 4 January 1983 • seven-year marketing exclusivity for approved orphan products (Marketing exclusivity prevents competition by preventing other companies from marketing the same drug for the same orphan indication.) • a tax credit of 50% of clinical trial costs • Orphan Products Grants Program • encourage manufacturers to develop and market drugs or biologics for diseases affecting relatively few people (fewer than 200,000 in the US). • ODA defines an "orphan drug" as one developed for a disease or condition that occurs so infrequently in the US that there is no reasonable expectation that the costs of research, development and marketing would be recovered from sales revenues. ODA expanded the definition of "orphan drugs" to include biological products, antibiotics, medical devices and medical foods. It also was amended to clarify the term "rare disease or condition" as any disease or condition in the US that affected: • fewer than 200,000 people (for vaccines and blood products, the figure of 200,000 or fewer applies to patients receiving the product annually) • more than 200,000 people and offering no reasonable expectation that the costs of development and distribution of the drug will be recovered from sale

Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act)

1984 Drugs • Provided abbreviated NDA (ANDA) process for generic drugs, requiring only bioavailability studies • Patent term restoration (extends term of a drug patent (only 1 of the patents), depending upon drug regulatory review period) • Marketing exclusivity for "pioneer" drugs (5 years NCEs; 3 years supplemental NDAs or new NDAs for marketed drug, both requiring new clinical data for approval) Section 505(b)(2) was added to the FD&C Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) to allow companies to develop alternative therapies more quickly by relying on existing data. • Applicants may rely on published literature that supports approval of an application and/or on FDA's previous finding of safety and effectiveness of an approved drug. • For example, a 505(b)(2) application can be submitted if the applicant has changed a product's route of administration from an oral form to an intramuscular injection. • In this instance, the applicant can rely on the efficacy data and some of the safety data established for the drug's oral formulation that has already been approved by FDA, but will have to conduct studies showing safety and efficacy that relate to the change to the intramuscular form. • In addition, the applicant will have to establish a "bridge" (e.g., via comparative bioavailability data) between the proposed drug and the approved listed drug to demonstrate that reliance on FDA's previous finding of safety and effectiveness is scientifically justified. • Sections 505(b)(2) and 505(j) of the FD&C Act together replaced FDA's "paper NDA policy," which had permitted an applicant to rely on studies published in the scientific literature to demonstrate the safety and effectiveness of duplicates of certain post-1962 pioneer drug products.

Safe Medical Devices Act (SMDA)

1990: Under the SMDA, device user facilities must report device related deaths to FDA and the manufacturer, if known. • Device user facilities also must report device-related serious injuries to the manufacturer, or to FDA, if the manufacturer is not known. • SMDA required that device user facilities submit to FDA, on a semiannual basis, a summary of all reports submitted during that time period. The device user facility reporting section of the SMDA became effective on 28 November 1991. • SMDA defined a "medical device" as "any instrument, apparatus, or other article that is used to prevent, diagnose, mitigate, or treat a disease or to affect the structure or function of the body, with the exception of drugs." • It instituted device tracking and postmarket surveillance equirements and allowed FDA to temporarily suspend or withdraw approval of an application for premarket approval. The rule provided civil penalties for violation of a requirement of the FD&C Act relating to devices. • The act amended the FD&C Act to create an incentive for the development of orphan or humanitarian use devices (HUDs), defined as devices for use in the treatment or diagnosis of diseases or conditions affecting fewer than 4,000 patients in the US each year. • introduction of the Humanitarian Device Exemption (HDE) • promulgation of the Quality System Regulation • establishment of a regulatory requirement that manufacturers and distributors promptly report field corrections and removals to FDA within 10 days after their initiation • promulgation of the first device tracking regulation

Prescription Drug User Fee Act (PDUFA)

1992 Drugs • authorized FDA to collect user fees from companies that produced certain human drug and biological products and submit applications for FDA review. • In addition, companies were required to pay annual fees for each manufacturing establishment and for each prescription drug product marketed. • Previously, taxpayers paid for product reviews through budgets provided by Congress. • In this program, industry provides the funding in exchange for FDA's agreement to meet drug review performance goals, which emphasize timeliness.

FDA Export Reform and Enhancement Act (FDERA)

1996 FDERA made certain regulatory changes that provide manufacturers with compliance options. When the minimum requirements of Section 801(e)(1) and either Section 801(e)(2) or one or more of the choices under Section 802 of the FD&C Act are met, FDA shall deem the devices to be not adulterated or misbranded for the purpose of export. There are two principal scenarios governing the export of investigational medical devices: a) exportation of Class I and/or Class II devices, and b) the exportation of Class III and/or banned devices. Both scenarios require, at a minimum, that the investigational devices to be exported meet the basic provisions of the FD&C Act, as now amendedin Section 801(e)(1). These provisions require that the device: • meet the foreign purchaser's specifications • not be in conflict with the importing country's laws • be labeled, "intended for export only" on the outside of the shipping package • not be sold or offered for sale in domestic commerce

FDA Modernization Act (FDAMA)

1997 Devices Drugs Biologics • Revised PHS Act and eliminated the ELA (Establishment License Application) for all biologics • FDAMA empowered FDA to restrict the marketing of products for which the manufacturing processes are so deficient that use of the products could present a serious health hazard. • The agency was given authority to take appropriate action if a device manufacturer advocates an off-label use of its product that may be potentially harmful. • FDAMA further enhanced FDA's risk-based approach to medical device regulation, allocating FDA resources and diligence to the oversight of medical devices presenting the greatest risks to patients. • exempts Class I devices not intended for a use that is of substantial importance in preventing impairment of human health or that do not present a potential unreasonable risk of illness or injury from premarket notification. • directs FDA to focus its postmarket surveillance on higher risk devices and allows the agency to implement a reporting system that concentrates on a representative sample of user facilities—such as hospitals and nursing homes—where patients may experience deaths and serious illnesses or injuries linked with the use of devices. • pilot program under which FDA accredits outside (third-party) experts to conduct the initial review of all Class I and low to- intermediate risk Class II device applications. • prohibits any accredited person from reviewing devices that are permanently implantable, life-supporting, life-sustaining or for which clinical data are required.

Medical Device User Fee and Modernization Act (MDUFMA)

2002 • Establishment inspections may be conducted by accredited persons (third parties) under carefully prescribed conditions. • New labeling requirements were established for reprocessed single-use devices. • The submission of validation data for some reprocessed single-use devices is required. On 30 April 2003, FDA identified the types of devices subject to this requirement (see 68 FR 23139).

The Pediatric Research Equity Act (PREA)

2003 Drugs Biologics PREA gave FDA clear authority to require pediatric studies of drugs when other approaches are insufficient to ensure drugs are safe and effective for children. If the course of a disease and the effects of the drug treatment for that disease are "sufficiently similar in adults and pediatric patients," FDA may waive the requirement if it can be concluded that "pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults."

Food and Drug Administration Amendments Act (FDAAA)

2007 Devices Drugs Biologics On 28 September 2007, as part of the Food and Drug Administration Amendments Act (FDAAA), user fees were reauthorized through Fiscal 2012.

Biologics Price Competition and Innovation Act (BPCI)

2009 • created an abbreviated approval pathway for biosimilars • Effective 30 June 2003, review of "well-characterized" or "therapeutic" biological products was transferred from CBER to CDER. • The review done by the appropriate therapeutic review division within CDER's Office of New Drugs (OND). • These products continue to be regulated as licensed biologics (i.e., BLA) per 21 CFR 601.2(a). • CDER also has responsibility for hormone protein products, e.g., insulin, growth hormone and pituitary hormones, as part of an October 1991 Inter-center Agreement between CBER and CDER; however, these products have been regulated as NDAs. However, under the Biologics Price Competition and Innovation Act (BPCI Act), proteins (with the exception of synthetic polypeptides) that have been approved as NDAs will be considered licensed biologics and will be required to comply with Section 351 of the PHS Act by March 2020, 10 years after the date of enactment of the BPCI Act.

Food and Drug Administration Safety and Innovation Act (FDASIA)

2012 Devices Drugs Biologics • The Food and Drug Administration Safety and Innovation Act (Public Law 112-144) included the Medical Device User Fee Amendments of 2012, or MDUFA III. • MDUFA III took effect on 1 October 2012 and reauthorized user fees through Fiscal 2017. • It added additional performance goals for FDA, as well as the issuance of several guidance documents tied to MDUFA III provisions including guidance on review actions taken on 510(k) and premarket approval applications. New fees include: • a fee for each 30-day notice submitted to FDA • a fee for each 513(g) request for classification information submitted to FDA • an annual fee for periodic reporting made under a condition of approval for a Class III device • an annual fee for the registration of each medical device establishment

In order of highest level to lowest level, the ranking at US governmental organizations is: A. Division, Office, Center, Agency, Department B. Department, Agency, Center, Office, Division C. Center, Department, Division, Agency, Office D. Agency, Center, Office, Department, Division

B. Department, Agency, Center, Office, Division

What products are exempt from the Prescription Drug User Fees Act (PDUFA)? A. Generic drugs only B. Orphan drugs and cosmetics only C. OTC drugs, cosmetics, generic drugs and medical devices D. Prescription drugs marketed before 1992

C. OTC drugs, cosmetics, generic drugs and medical devices