sept 28th Federal Regulation of Medications: FDA Amendments

Federal Food, Drug, and Cosmetic Act (FDCA)

• 21 USC 301 et seq

• provides for the comprehensive regulation of all drugs introduced into interstate commerce.

• The intent of the law is to protect consumers from adulterated or misbranded foods, drugs, cosmetics, or devices.

• Under the Act, no new drug may be marketed and sold unless it has been proved both safe and effective for its intended use and approved by the federal Food and Drug Administration.

Pure Food and Drug Act of 1906

• concern for the risks to public health and safety associated with unsanitary and poorly labeled foods and drugs prompted Congress in 1906 to pass the Pure Food and Drug Act

• The law prohibited the adulteration and misbranding of foods and drugs in interstate commerce

• In 1912, the Act was amended to prohibit false and fraudulent efficacy claims.

• The act failed to achieve its purpose.

• Difficult to enforce because it required the government to prove fraudulent intent on the part of one who made false statements on the label.

Sulfanilamide elixir tragedy of 1937

• Sulfanilamide was one of the first of the “miracle” anti-infective sulfa drugs marketed.

• Manufacturer produced the drug in an elixir form with diethylene glycol as a solvent.

• No toxicity tests had been conducted.

• Solvent was a found to be a deadly poison and 107 deaths were attributed to this elixir.

Pure Food and Drug Act of 1906 cont

CONT

• The 1906 law had not granted the FDA the authority to ban unsafe drugs.

• FDA removed the elixir on a technicality.

  • Elixirs must contain alcohol, the elixir of sulfanilamide did not contain alcohol.

Food, Drug, and Cosmetic Act of 1938 (FDCA)

• The FDCA with Amendments forms the nucleus of today’s law.

• Provided that no new drug could be marketed until proved safe for use under the conditions described on the label and approved by the FDA.

• The law expanded the definition of misbranding and adulteration under the earlier act.

• Labels must contain adequate directions for use and warnings about the habit-forming properties of certain drugs.

• Applies to cosmetics and devices as well.

Durham-Humphrey Amendment of 1951

• The 1938 FDCA required all drugs to be labeled with “adequate directions for use.”

  • Drugs on the market at this time were not safe for use except under medical supervision.

• Durham-Humphrey Amendment was enacted to solve this problem

• Amendment established two classes of drugs

  • prescription and over the counter

• Provided that the labels of prescription drugs need not contain “adequate directions for use” so long as they contain the legend, “Caution: Federal law prohibits dispensing without a prescription”

• When dispensed by a pharmacist, inclusion on the label of directions from the prescriber satisfies the “adequate directions for use” requirement.

• Amendment also authorizes oral prescriptions and refills of prescription drugs.

Additives Amendment of 1958

• Congress amended the FDCA to require that components added to food products must receive premarket approval for safety.

• Anticancer provision, (Delaney Clause)

  • prohibits the approval of any food additive that might cause cancer.

Color Additive Amendments of 1960

• Requires manufacturers to establish the safety of color additives in foods, drugs, and cosmetics.

• The FDA can approve a color for one use but not the others (e.g. external use only)

Thalidomide

• 1950’s a popular sedative was being marketed in Europe.

• The FDA withheld final approval of the new drug application (NDA) pending safety information.

• In 1961, confirmed that thalidomide caused a birth defect, in thousand of infants.

• Due to the FDA refusal to allow marketing of the drug in the US, the number of birth defects in the US was low.

• Congress enacted the Kefauver-Harris Amendment

Kefauver-Harris Amendment of 1962

• Strengthened the new drug approval process by requiring drugs to be proved not only safe but also effective.

• The efficacy requirement was made retroactive to all drugs marketed between 1938 and 1962.

• Amendment also:

  • transferred jurisdiction of prescription drug advertising from the Federal Trade Commission to the FDA

  • established the Good Manufacturing Practices (GMP) requirements

  • added more extensive controls for clinical investigations

    • informed consent

    • reporting of adverse drug reactions

Medical Device Amendment of 1976

• Under the 1938 Act, the FDA had no authority to review medical devices for safety and efficacy before marketing

• Prompted by public safety concerns with certain devices, Congress amended the FDCA in 1976 to provide for more extensive regulation administrative authority regarding the safety and efficacy of medical devices.

• Amendment requires:

  • classification of devices according to their function

  • premarket approval

  • establishment of performance standards

  • conformance with GMP regulations

  • adherence to record and reporting requirements

Orphan Drug Act of 1983

• Pharmaceutical manufacturers had urged Congress to recognize that the NDA process was too expensive to warrant development and marketing of drugs for diseases that affected few people.

• In 1983, Congress passed legislation to provide tax and exclusive licensing incentives for manufacturers to develop and market these drugs or biologicals

• “rare diseases or conditions” (defined as those affecting fewer than 200,000 Americans.)

Drug Price Competition and Patent Term Restoration Act of 1984

• Waxman-Hatch Amendment

• Enacted to streamline the generic approval process while giving patent extensions, in certain circumstances, to innovator drugs.

• The intent is to make generic drugs more readily available to the public while providing incentives to manufactures to develop new drugs.

Prescription Drug Marketing Act of 1987

• Due to growing alarm that a secondary distribution system for prescription drugs was threatening the public health and safety and creating an unfair form of competition.

• Law establishes sales restrictions and record keeping requirements for prescription drug samples.

• Prohibits hospitals and other health care entities from reselling their pharmaceuticals to other businesses and requires state licensing of drug wholesalers.

Safe Medical Devices Act of 1990

• This act further strengthened the Medical Device Amendment giving the FDA additional authority especially related to post marketing requirements and premarket notification and approval, while expediting the premarket device approval process.

The Generic Drug Enforcement Act of 1992

• Occurred when some FDA staff accepted bribes from generic drug industry personnel in order to facilitate the approval process of certain generic drug products.

• FDA to ban individuals or firms from participating in the drug approval process if convicted of related felonies.

• Imposes severe civil penalties for any false statements, bribes, failures to disclose material facts and other related offenses.

Prescription Drug User Fee Act fo 1992

• The FDA and Congress took the approach that private industry should shoulder part of the costs for new drug approval rather than the taxpayers.

• Requires manufacturers to pay fees for applications and supplements when the FDA must review clinical studies.

• Fees provide the FDA with the resources to hire more reviewers to assess these clinical studies and hopefully speed up the NDA review.

Nutrition Labeling and Education Act of 1990 (NLEA)

• Mandates nutrition labeling on food products and authorizes health claims on product labeling, as long as they are made in compliance with FDA regulations

Dietary Supplement Health and Education Act of 1994 (DSHEA)

• Dietary supplement manufacturers felt that the NLEA left too much authority with the FDA and unduly restricted the promotion of dietary supplements.

• DSHEA defines dietary supplements and permit manufacturers to make certain claims that otherwise would have been illegal under the FDCA,

• FDA to regulate dietary supplements more as foods than as drugs.

Dietary Supplement

• A product that is intended:

  • For ingestion;

  • To supplement the diet;

  • Contains any one or more of the following:

    • a vitamin

    • a mineral

    • an herb or other botanical

    • an amino acid

    • a dietary substance for use by humans to supplement the diet by increasing the total dietary intake

    • a concentrate, metabolite, constituent, extract, or combination of the previous

• Manufacturers may make limited health claims for dietary substances that describe the relationship between a food substance and a disease.

  • “folic acid may reduce the risk of neural tube birth defects”

• To make the claims, the manufacturer must receive FDA approval for the health claim as judged by the “significant scientific agreement” standard.

• Today, the FDA has appeared to relax its standard for evaluation, stating it would approve such claims if the scientific evidence in support of the claim outweighs the evidence against the claim

Food and Drug Administration Modernization Act of 1997 (FDAMA)

• Due to FDA criticism, the FDA was not efficiently administrating its statutory responsibilities and that the FDCA was too burdensome a regulatory system for drug approval.

• FDAMA passed to streamline regulatory procedures to ensure the expedited availability of safe and effective drugs and devices.

• The intent is eliminate backlogs in the approval process and ensure timely review of applications.

• Creates fast track approval process for drugs intended for serious or life threatening diseases, establishes a database of information on clinical trials, authorizes scientific panels to review clinical investigations and expands the rights of manufacturers to disseminate unlabeled use information.

• Expands the FDA’s authority over OTC drugs and establishes ingredient labeling requirements for inactive ingredients

Medical Device User Fee and Modernization Act of 2002

• This act established user fee requirement for premarket reviews of medical devices and also established  performance goals for many types of premarket reviews, inspections that can be conducted at establishments by accredited third parties and new regulatory requirements for reprocessed single use devices.  This also must be renewed by Congress every 5 years

Food and Drug Administration Amendments Act of 2007 (FDAAA)

• FDA broader use of the fees generated from PDUFA, substantially increasing fees

• In response to postmarket problems with certain drug products (ie Vioxx), the law provides FDA with increased responsibilities and authority to regulate drug safety, label changes related to safety, clinical trial data reporting and registries, requiring postmarket clinical studies to assess risk and requires companies to implement risk evaluation and mitiation strategies (REMS).

FDA Safety and Innovation Act of 2012

• The law allows the FDA to continue to collect fees from manufacturers seeking NDAs or medical device approvals. 

• It also adds the Generic Drug User Fee Act and Biosimilar User Fee Act. 

• The purpose of imposing fees on these manufacturers is to increase resources for the FDA in order to speed the generic drug and biosimilar approval process. 

• The law also contains several provisions directed at reducing drug counterfeiting, blocking the import of adulterated products, detecting and reducing drug shortages, and enhancing the exchange of prescription drug diversion information across state lines.  Additionally this law enables the FDA to inspect foreign drug manufacturers more regularly and requires the agency to target problematic manufacturing sites

Drug Quality and Security Act of 2013

• Two titles under this act.  Title 1 also called the Compounding Quality Act, clarifies and strengthens FDA oversight over pharmacies engaged in the large scale compounding and shipping of sterile products to other licensed entities. 

• The law also removed uncertainty regarding when a product compounded by a pharmacy is exempt from CGMP, labeling and the new drug approval process. 

• Title II known as the Drug Supply Chain Security Act, adds “track and trace” requirements for all entities in the chain of distribution of pharmaceutical products.  Requires manufacturers to provide transaction information to purchasers, who in turn must provide transaction information to subsequent purchasers. 

• The law also mandates an electronic, interoperable product tracing system by 2023, strengthens wholesaler and third party logistics licensure requirements and requires manufacturers to serialize drugs by 2017.

The 21st Century Cures Act of 2016

• This Act was passed in large part to streamline and add flexibility and innovation to the drug development and approval process, primarily by creating new clinical trial design options and by accelerating the pathways to market for drugs intended to treat certain serious or life threatening diseases.  This law also provides for billions of dollars of additional funding to the National Institute of Health (NIH).

FDA Reauthorization Act of 2017

• This act reauthorized the user fee programs and enhanced the goals of the Cures Act and created a new category of OTC hearing aids.

Rationale for Federal Drug Regulation

• Protection of the public against adulterated and misbranded drug products

• Necessity of balancing “direct regulation” and “indirect regulation”

Federal Food and Drug Administration (FDA)

• Housed under the Department of Health and Human Services (HHS)

• Authority for administering the FDCA

• FDA secretary appointed by president with confirmation of Senate

Structure of FDA

• National headquarters and extensive field force

• Nine Center level organizations and Thirteen Headquarter Offices

FDA Centers and Offices

• The Center for Drug Evaluation and Research (CDER)

• The Center for Biologics Evaluation and Research (CBER)

• The Center for Devices and Radiological Health (CDRH)

• The Center for Food Safety and Applied Nutrition (CFSAN)

• The Center for Tobacco Products

• The Center for Veterinary Medicine

• The National Center for Toxicological Research

• The Oncology Center of Excellence

• The Office of Regulatory Affairs and

• The Office of Operations

Functions of FDA

• Rulemaking

• Issue guidance documents

• Incorporate advice from standing advisory committees of outside experts

the term food means:

• articles used for food or drink for man or other animals;

• chewing gum; and

• articles used for components of any such article.

what is a drug?

• Drug definition

  • Intended use: Therapeutic claims and structure/function claims

• Evidence of intended use

drug

• A.  Articles recognized in the US Pharmacopeia, official Homeopathic Pharmacopeia of the US, or official National Formulary, or any supplement to any of them; and

• B.  articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and

• C.  articles (other than food) intended to affect the structure or any function of the body of man or other animals; and

• D.  articles intended for use as a component of any articles specified above

• Broad meaning

• Addresses products intended for use with diseases;

• Recognizes that even products not intended for use with diseases may still be drugs if they make a structure or function claim.

Critical issue of determining if a product is a drug

• Test: Determine whether a product is a drug centers on whether the supplier made a therapeutic claim.

  • Was the article intended to diagnose, cure, mitigate, treat, or prevent a disease, or was it intended to affect the body structure or function?

  • If therapeutic claims are made, an article is a drug.

hypo

• A company that manufacturers alfalfa pellets for animals may decide to produce alfalfa tablets for humans, claiming that the tablets will cure ulcers and other GI disorders.  The label specifically notes that the tablets are not drugs.  Would a court consider the tablets to be a drug?

• A hardware store sells DMSO, an industrial solvent, to Mary.  Mary intends to purchase the DMSO and apply it externally to reduce joint pain.  The hardware store does not make any therapeutic claims.  In this situation is DMSO a drug?

counterfeit drug

• A drug which, or the container or labeling of which, without authorization, bears the trademark, trade name, or other identifying mark, imprint, or device, or any likeness thereof, of a drug manufacturer, processor, packer, or distributor other than the person or persons who in fact manufactured, processed, packed, or distributed such drug and which thereby falsely purports or is represented to be the product of, or to have been packed or distributed by, such other drug manufacturer, processor, packer or distributor.

device

• An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is:

  • recognized in the official National Formulary, or the US 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 any of its principal 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 principal intended purposes.

cosmetic

• Articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and

• articles intended for use as a component of any such articles;

• except that such term shall not include soap

label

• A display of written, printed, or graphic matter upon the immediate container of any article; and a requirement made by or under authority of the FDCA that any word, statement, or other information appearing on the label shall not be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper.

labelling

• All labels and other written, printed, or graphic matter

  • upon any article or any of its containers or wrappers, or

  • accompanying such article

• Broad application

• Includes the label and information accompanying the drug

  • Package insert

• Accompanying = labeling

• Not accompanying = advertising

official compendia

• United States Pharmacopeial Convention: USP

  • Organization and function

  • Role and legal authority of the USP

• Homeopathic Pharmacopoiea of the United States

  • Organization and function

  • Role and legal authority of HPUS

Prohibited Acts, Penalities, and Enforcement under FDCA

• Prohibited Acts

  • The introduction or delivery for introduction into interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded.

  • The adulteration or misbranding of any food, drug, device, or cosmetic in interstate commerce.

  • The receipt in interstate commerce of any food, drug, device, or cosmetic that is adulterated or misbranded, and the delivery or proffered delivery thereof for pay or otherwise.

  • The introduction or delivery for introduction into interstate commerce of any article in violation of the FDCA.

  • The refusal to permit access to or copying of any record as required … or the failure to establish or maintain any record, or make any report, required … or the refusal to permit access to or verification or copying of any such required record.

  • The refusal to permit entry or inspection.

  • The manufacturer within any Territory of any food, drug, device, or cosmetic act that is adulterated or misbranded.

  • The doing of any act which causes a drug to be a counterfeit drug, or the sale or dispensing, or the holding for sale or dispensing, of a counterfeit drug.

  • The adulteration, mutilation, destruction, obliteration, or removal of the whole or any part of the labeling of, or the doing of any other act with respect to, a food, drug, device, or cosmetic, if such act is done while such article is held for sale, after shipment in interstate commerce and results in such article being adulterated or misbranded.

  • The introduction or delivery for introduction into interstate commerce of a dietary supplement that is unsafe under the FDCA.

penalities

• Violator shall be:

  • imprisoned for more than 1 year

  • fine not more than $1,000

  • or both fines and imprisonment

• Second Offense or intent to defraud or mislead

  • imprisonment up to 3 years

  • fine up to $10,000

two major offenses under FDCA

• Adulteration

• Misbranding

• Violations are Strict Liability in nature

adulterated drugs

• A drug may be adulterated under the FDCA, even if it is pure, because a drug is deemed adulterated if it is:

  • prepared, packed, or held in conditions where it may have been contaminated

  • exposed to a container that may have been contaminated it

  • or manufactured under conditions that do not conform to current Good Manufacturing Practice (CGMP)

• Apply to manufacturers, however, a pharmacy may be deemed a manufacturer if:

  • it repackages or

  • compounds medications for sale under certain conditions.

• A drug is adulterated if it contains an unsafe color additive, or if its strength, quality or purity differs from standards, unless stated on the label.

misbranding

• The FDA must approve, as part of the premarket approval process, the exact wording of a drug’s label and labeling.

• The labeling shall:

  • not be false or misleading;

  • provide established names of drugs

    • listing of any active ingredient for both prescription and OTC drugs

  • adequate directions for use

    • directions under which a layperson can use a drug safely and for the purposes for which it is intended

  • adequate information for use

  • not be an imitation drug

new drug approval

• No person may introduce a “new drug” into interstate commerce unless approved by the FDA.

• “New drug” is defined as a drug that is not generally recognized by qualified experts as safe and effective (GRASE) for use under the conditions recommended in the drug’s labeling and has been used for a material extent and time for conditions recommended in labeling.

• The FDA will not accept a GRASE application and requires a new drug application.

approved drugs as new drugs

• An approved drug can become a new drug under certain conditions:

  • Addition of new substance

  • New combination of approved drugs

  • Change in proportion of ingredients

  • New intended use

  • Dosage, method, or duration of administration or application is changed

new drug application (NDA) process

• Investigational New Drug (IND) Application

  • The sponsor must receive approved Notice of Claimed Investigational Exemption for a New Drug in order to ship drug in interstate commerce to conduct phase 1, 2, and 3 clinical studies.

  • The FDA may terminate testing at any time under risk–benefit criteria; the decision is not subject to appeal or judicial review.

  • The FDAAA requires NDA sponsors to publish summary information regarding phase 1 trials on a public registry.

informed consent

• Informed consent required in all three phases

• Research subjects required to know risks, possible benefits, and alternative courses of treatment

• Institutional Review Board (IRB) approval required in some settings

new drug application (NDA)

• The FDA has 180 days to act on a completed NDA, but delays are common.

• Approval is based on proof of safety and efficacy, the manufacturing process, and risk–benefit ratio.

• Applicant may judicially appeal a rejected NDA, but success is very unlikely.