Exam 1-chapter 2 Law

Pure Food and Drug Act of 1906

- Concern public health and safety - 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 of false statements on the label manufacturer. *****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)

Supplemental New Drug Applications: Minor changes

.such as editorial changes in the labeling or changes in container size.

Food and Drug Administration Modernization Act of 1997 (FDAMA) Impetus

--FDA was criticized for being not efficiently administrating its statutory responsibilities and being burdensome a regulatory system for drug approval. FDAMA: - to streamline regulatory procedures to ensure the expedited availability of safe and effective drugs and devices. 1/eliminate backlogs in the approval process 2/ ensure timely review of applications.

Supplemental New Drug Applications: Production

.synthesis of drug, manufacturing process of the drug most labeling a "prior approval' supplement is required .FDA must approve the change before the manufacturer can implement it

DSHEA Criticism

-allows the marketing of unsafe dietary supplements prevents the FDA from acting aggressively enough to protect the public. --Lack of consumer information about the dangers of taking supplements with certain OTC and Rx medications. --Lack quality standards for strength and purity

Current Good Manufacturing Practice (CGMP)

..A drug is adulterated unless it is manufactured in accordance with CGMP. ..CGMP is a set of regulations that establishes the minimum requirements for the methods, facilities, or controls used to manufacture, processing, packaging, or holding of a drug product.

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.

Imitation Drugs

..A product is an imitation if it is: ..identical in shape, size and color ..similar or virtually identical in gross appearance ..similar in effect to controlled substances

Substantial Evidence

..Adequate and well controlled investigations by experts qualified by scientific training and experience to evaluate the drug's effectiveness.

Two major offenses under FDCA

..Adulteration ..Misbranding ..Violations are Strict Liability in nature (no excuse e.g: speeding)

Supplemental New Drug Applications

..After the approval of an NDA, a manufacturer may not make any changes in the drug or it production. ..Three procedural categories: production, labeling changes, minor changes

Labeling 21 USC sec 321 (m)

..All labels and other written, printed, or graphic matter ..upon any article or any of its containers or wrappers, or ..accompanying such article

New Drug Application

..Also known as NDA ..Contains the complete evaluation of the drug's safety and efficacy. ..Hundred of thousands of pages ..FDA has 180 days to act on a completed NDA ..Delays are common ..Manufacturers rarely launch a legal challenge ..FDA proposes to disapprove an NDA, notify the applicant and provide an opportunity for hearing

Approved Drugs as "New Drugs"

..An Approved drug may become a new drug if: ..The drug contains a new substance (e.g. active ingredient, excipient, carrier or coating) ..There is a new combination of approved drugs ..The proportion of ingredients in combination is changed ..There is a new intended use for the drug ..The dosage, method, or duration of administration or application is changed. 

FDA Approval Process

..Applicant must submit evidence to the FDA that shows that the drug is safe and effective. ..Conduct animal and clinical studies.

Labeling

..Broad application ..Includes the label and information accompanying the drug ..Package insert ..Accompanying = labeling ..Not accompanying = advertising

Tamper Resistant Package

..Defined as one having an indicator or barrier to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred.

Tampering

..Defined in the act as improper interference with the product for the purpose of making objectionable or unauthorized changes.

Clinical Study Phase III

..Drug is tested for safety and efficacy in hundreds or even thousands of patients. ..Clinical settings ..Usually the study is double blinded and compared with a control group. ..Phase IV ..Postmarketing surveillance activities ..FDA required manufacturers to conduct clinical studies after the drug is approved ..The FDA may terminate testing of an IND at any time if studies show that the drug is too toxic under the agency's benefit/risk ratio.

FDA Rating and Classification System

..FDA utilizes a priority classification system that rates new drugs by chemical type and therapeutic potential. ..Determines how rapidly the drug will proceed through the NDA process.

Informed Consent

..FDCA requires investigators to obtain the informed consent of the study subject or a representative for the administration of an experimental drug. ..Informs the subject about the risks, benefits and alternative treatments. ..IRB approval of the study

Clinical Study Phase II

.Tested on a limited number of patients who actually have the disease for which the drug is an intended treatment. .Purpose is to determine the efficacy of the drug and the dosages at which efficacy occurs. .Pharmacological testing to determine the drug's safety.

Product Tampering

..Federal Anti-Tampering Act (18 USC sec 1365) ..Federal offense to tamper with consumer products ..Requires certain OTC drugs, cosmetics, and devices be manufactured with tamper resistant packaging. ..Violation may result in misbranding, adulterated, or both. ..Tylenol poisoning in 1980's Product Tampering ..Federal Anti-Tampering Act (18 USC sec 1365) ..Federal offense to tamper with consumer products ..Requires certain OTC drugs, cosmetics, and devices be manufactured with tamper resistant packaging. ..Violation may result in misbranding, adulterated, or both. ..Tylenol poisoning in 1980's

Adequate Information for Use

..Labeling must include: ..drug indication ..side effects ..dosages ..routes, methods, frequency, and duration of administration ..contraindication ..other warnings

Adequate Directions for Use

..Labeling of drug must include ..the quantity or dosage for each intended use and for persons of different ages and physical conditions ..the frequency of administration or application ..the duration of administration or application ..the time of administration or application ..route or method of administration or application ..the preparation necessary for use (shaking)

IND Application

..List experience and qualifications of the clinical investigators ..Study protocol ..Purpose is to protect the safety of the humans who will participate in the clinical trials and to ensure that the clinical studies are designed properly to prevent problems during the NDA review.

New Drug Approval Background

..No "new drug" can be legally marketed in interstate commerce unless it has been approved by the FDA. ..FDA requires drug manufacturers to apply for and receive FDA approval of a New Drug Application (NDA) ..Expensive and lengthy process

Section 505(a) of FDCA

..No person shall introduce into interstate commerce any "new drug" unless an application has been approved by the FDA.

Postmarketing Surveillance

..Once a drug has been approved, the manufacturer may legally distribute the drug in interstate commerce. ..Section 505(k) of the FDCA requires that the manufacturer maintain and establish postmarketing records and reports ..Submit to the FDA reports of any serious adverse drug reactions and new information relating to the drug's safety and efficacy.

MEDWATCH

..Purpose ..Importance of health care professionals reporting ..What should be reported

MARKETED UNAPPROVED DRUGS

..Reasons why unapproved drugs are on the market today ..FDA approach to these drugs ..Ramifications for pharmacists 

1938 FDCA

..Required drugs to be proved to be safe before the FDA granted marketing approval ..1962 Kefauver Harris amendment to FDCA required that drugs be proved not only safe but also effective

Section 505(d) of the FDCA

..Requires applicants to submit adequate information to demonstrate the drug's safety for use under the conditions prescribed, recommended or suggested in the proposed labeling. ..Efficacy: stipulates that the applicant must submit "substantial evidence that the drug will have the effect it purports or is represented to have under the conditions or use prescribed, recommended, or suggested in the proposed labeling."

"New Drug"

..Section 201(p) of the FDCA defines New Drug. ..A Drug that is not generally recognized by qualified experts as safe and effective for use under the conditions recommended in the drug's labeling. ..A drug marketed before 1938 is exempt from proving either safety or efficacy provided that it is marketed in accordance with the labeling requirements as then existed.

Pregnancy Warning

..See textbook ..Category A ..Category B ..Category C ..Category D ..Category X

Misbranding

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

Prohibited Acts, Penalties, and Enforcement under FDCA

..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. ..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.

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

Penalties under FDCA

..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

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

Clinical Study Phase I

.Involves a small number of subjects .Investigators examine the drug toxicity, metabolism, bioavailability, elimination and other pharmacological actions. .Purpose is to detect adverse effects, not efficacy.

Clinical Study Phase IV .

.Postmarketing surveillance activities ..FDA required manufacturers to conduct clinical studies after the drug is approved ..The FDA may terminate testing of an IND at any time if studies show that the drug is too toxic under the agency's benefit/risk ratio.

Supplemental New Drug Applications: Labeling changes

.Strength warnings or dosage and administration information, or for certain changes in manufacturing methods, facilities, and controls, a "change being effected" supplement may be allowed. .Allows Manufacturer to implement the change before FDA approves it.

Food and Drug Administration Modernization Act of 1997 (FDAMA)

1/ Creates fast track approval process( for serious or life threatening diseases) 2/ establishes a database of information on clinical trials 3/ authorizes scientific panels to review clinical investigations 4/ expands the rights of manufacturers to disseminate unlabeled use information. 5/ Expands the FDA's authority over OTC drugs 6/ establishes ingredient labeling requirements for inactive ingredients.

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

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

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. 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.

Drug Definition

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

Label 21 USC sec 321 (k)

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.

Counterfeit Drug 21 USC sec 321 (g)

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.

Dietary Supplement Defintion

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

Durham-Humphrey Amendment of 1951

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.

Device 21 USC sec 321

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 21 USC sec 321 (i)

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

Drug

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.

Food 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.

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.

OTC DRUG REVIEW

Distinguish the process from that of the DESI review for prescription drugs See Textbook Category I Category II Category III

HEALTH CLAIMS FOR FOODS

Drug Issue NLEA provision FDAMA provision FDA regulation

WHAT IS A DRUG?

Drug definition Intended use: Therapeutic claims and structure/function claims Evidence of intended use

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.

Food and Drug Administration Amendments Act of 2007 (FDAAA)

FDA broader use of the fees generated from PDUFA, substantially increasing fees -postmarket problems with certain drug products (ie Vioxx) --> 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 --requires companies to implement risk evaluation and mitigation strategies (REMS)

The Generic Drug Enforcement Act of 1992

FDA staff accepted bribes from generic drug industry FDA to ban convicted individuals from participating drug approval process. Imposes severe civil penalties for any false statements, bribes, failures to disclose material facts and other related offenses.

FOOD OR DRUG?

Food Definition Meaning of exclusion from part C of drug definition

Clinical Study phases

Four phases

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

Investigational New Drug Application (IND Application)

Manufacturer submits to the FDA a substantial amount of information: ..The name of the drug ..Its composition ..Methods of manufacture and quality control ..Information from preclinical (animal) investigations regarding pharmacological, pharmacokinetic and toxicological evaluations

Dietary Supplement (claim making)

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.

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

Prescription Drug User Fee Act of 1992

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 to hire more reviewers to assess these clinical studies and hopefully speed up the NDA review

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

SPECIAL FOOD CATEGORIES

Special dietary foods Medical foods Nutraceuticals & functional foods

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

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.

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.

Blackbox Warning

Textbook

NATIONAL DRUG CODE NUMBER

Textbook

Durham-Humphrey Amendment of 1951 Impetus

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

Product Recalls

Three classes of recalls: ..Class I-recalls are issued when there is a reasonable probability that the product will cause serious, adverse health consequences or death. ..Class II-recalls occur when the product may cause temporary or medically reversible health consequences, but the probability of serious adverse consequences is remote. ..Class III-recalls apply to products that are not likely to cause adverse health consequences. ..The manufacturer is responsible for notifying the sellers of the recall. ..The sellers are responsible for contacting the consumers. ..A pharmacist is responsible for knowing which drug products have been recalled.

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

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.

Section 201 of the FDCA (21 USC sec 321(f)) Food means?

articles used for food or drink for man or other animals; chewing gum; and articles used for components of any such article.

EXPEDITED APPROVAL PROCESS

•Criteria •Requirements •See textbook