Federal Regulation of Medication

Supplemental New Drug Application (SNDA)

-Submitted after NDA approval -Covers changes in synthesis, production procedures, manufacturing locations, packaging, labeling, indications

Unit Dose Labeling

-Unit Dose blister pack-strip of individual cells or sheet, but usually small and often torn apart, punctured, or removed from outer carton. FDA recommends: -Blister cell label: When possible: -Proprietary and established name, -strength, (quantity of active ingredient in each dosage unit -lot number, -expiration date, -bar code and -Name of manufacturer should appear over each blister. Alternative: random display of the information can appear multiple times across the back of the blister, or the important information should be displayed so that it is not destroyed or eliminated when dosage units are removed -Product strength-the blister carton labeling should describe the milligram amount of drug per single unit (i.e., tablet, capsule).

Food and Drug Administration Modernization Act 1997

-passed to streamline regulatory procedures. -Created fast-track approval process for drugs intended to treat life threatening or serious diseases -Use of expert panels in drug approval process (scientific review panels for clinical investigations) -Expands FDA's authority over over-the-counter drugs and established ingredient labeling requirements for inactive ingredients

Nonprescription Labeling Requirements

(Can refer to slide 24 of federal regulation of medication ppt for example image) -Below is an example of what the new OTC medicine label looks like. -Active Ingredient: Therapeutic substance in product; amount of active ingredient per unit -Purpose: Product action or category (such as antihistamine, antacid, or cough suppressant. -Uses: Symptoms or diseases the product will treat or prevent. -Warnings: When not to use the product; conditions that may require advice from a doctor before taking the product; possible interactions or side effects; when to stop taking the product and when to contact a doctor; if you are pregnant or breastfeeding, seek guidance from a health care professional; keep product out of children's reach. -Directions: Specific age categories, how much to take, how to take, and how often and how long to take. -Other Information: How to store the product properly and required information about certain ingredients (such as the amount of calcium, potassium, or sodium the product contains -Inactive Ingredients: Substances such as colors or flavors.

Adequate labeling and directions for use

-Adequate labeling must include: i. Quantity or dosage for each intended use and for persons of different ages and physical conditions ii. Frequency of administration/application iii. Duration of administration/application iv. Time of administration/application (in relation to meals, onset of symptoms, or other factors) v. Route or method of administration or application vi. The preparation necessary for use (shaking, dilution, etc.) -Adequate information for use- some drugs can't be labeled adequately to protect the consumer (prescription drugs) which makes them exempt. Label must include: a. Drug's indications b. Side effects c. Dosages d. Routes, methods, frequency, and duration of administration e. Contraindications f. Other warnings and precautions that enable a practitioner to administer, prescribe or dispense the drug safely

Labeling

-All labels and other written, printed, or graphic matter on any container or wrapper or material accompanying the product Includes: Package insert -If information accompanies (comes with the article) its labeling, if not, its advertising

Nutrition Labeling and Education Act 1990

-Allowed the use of FDA approved health claims on food labels and required a uniform label that includes serving size, contents calories, nutrients, and the recommended daily allowance of nutrients for which such daily values have been established, lists of ingredients and the number of servings per containers. -Health claims are limited to claims about disease risk reduction, and cannot be claims about the diagnosis, cure, mitigation, or treatment of disease. Health claims are required to be reviewed and evaluated by FDA prior to use. An example of an authorized health claim, is: "Three grams of soluble fiber from oatmeal daily in a diet low in saturated fat and cholesterol may reduce the risk of heart disease. This cereal has 2 grams per serving.

Manufacture to Consumer (Direct to Consumer (DTC))

-Broadcast media: 1. Advertise summary of risks in audio and video form as long as there is an "adequate provision" for the consumer to obtain full labeling information through a multifaceted approach from four sources (suggested to use all four): a. Toll free number b. Internet webaddress c. Referral to print advertisement in a concurrently running print publication or available brochures d. Referral to a health care professional - Print advertising 1. Suggested to list the most serious and common risks associated with the product in consumer user friendly way a. Modification of approved patient labeling such as package insert or MedGuides OR b. Include information contained in highlights section of the package insert -Three categories of ads 1. Product claim ads a. Name the drug and the condition it treats and are subject to regulations 2. Reminder ads a. Name the drug but not uses; are not subject to regulations 3. Health seeking ads a. Educational in nature and do not mention name of product only the name of the company b. Generally inform the consumer about the disease, mentioning that a physician can treat a particular condition with medications and urge consumer to see physician. c. No subject to regulation

Pregnancy Categories

-Category A: Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). -Category B: Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. -Category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. -Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. -Category X: Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits

When is a product a drug?

-Did supplier make a health or therapeutic claim or a structure/function 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? -Look at the claims of the product in advertising/marketing -Mere use by purchasers, where the SUPPLIER DOES NOT INTEND THE PRODUCT TO BE USED THERAPEUTICALLY OR MAKES NO THERAPEUTIC CLAIMS, doesn't make the article a drug

NDC code

-Drug Listing Act of 1972: requires manufacturers provide the FDA with a current list of all drugs manufactured, prepared, propagated, compounded, or processed by it for commercial distribution. -Drug products are identified and reported using unique 11 digit, three segment number used to identify the manufacturer, the drug, and the package size. -NDC number: 1234-5678-90 a. 1234=Manufacturer b. 5678=drug c. 90=package

Drug advertising and commercial speech (1st amendment right to free speech)

-Drug advertising is commercial speech, so questions are what advertising, what manner, and to what extent -Commercial speech- promotional activities by product sellers is governed by Central Hudson test 1. Speech must not be misleading or related to unlawful activity 2. Government interest in the regulation must be substantial 3. Regulation must directly advance the government interest asserted 4. The restriction cannot be more extensive than necessary to serve the interest

New Drug Application (NDA)

-Drug manufacturers must apply for and receive FDA approval of a new drug application (NDA), if the drug is not a generic of a currently marketed drug -Required Information in NDA application: a. Full reports of investigations showing the drug's safety and efficacy b. The drug's components and composition c. The methods, facilities, and controls used in manufacturing, processing and packaging the drug. d. Samples of the drug and its components e. The proposed labeling of the drug

Investigational New Drug (IND) Application

-Proposal for IND includes: a. drug information 1. Name 2. Composition 3. Methods of manufacture and quality control 4. Information from preclinical (animal) investigations regarding pharmacological, pharmacokinetic, and toxicological evaluations ii. Investigator/investigation information 1. Experience and qualifications of clinical investigators, 2. Outline of proposed clinical trials b. Testing- three phases; investigators must obtain informed consent from patient, and patient representative. Written consent for phase 1 and 2, oral consent is permitted during phase 3 if physician decides its necessary or preferable to written consent and consent is documented in medical chart. i. Phase 1- detect adverse effects (toxicity, metabolism, bioavailability, elimination, pharmacological actions), not test efficacy ii. Phase 2- determine efficacy of the drug and the dosages at which efficacy occurs iii. Phase 3-tested for safety and efficacy in hundreds or thousands of patients

Advertising to Professionals

-FDCA section 502(n) provides that a drug shall be deemed misbranded unless the manufacturer includes in all advertisements and other descriptive printed matter issued a true statement of: a. The established name of the drug b. The formula showing quantitatively each ingredient c. A brief summary of other information relating to side effects, contraindications, and effectiveness d. True statement: i. Is not false or misleading ii. Is a fair balance between side effects and contraindication information and effectiveness information iii. Reveals material facts -Advertising includes journal and other periodical ads, media ads, telephone communications. 1. Brochures, booklets, mailing pieces, bulletins, calendars, price list, references and other such information disseminated by manufacturer for use by health care professionals are considered LABELING. a. Advertising only contain brief summary of risks b. Labeling must include the entire package insert c. Media advertising- only major risks, provided manufacturer makes adequate provision for the dissemination of the approved package labeling. -Industry sponsored educational programs distinguished from promotional programs- 1. Concern- objectivity of some manufacturer supported educational programs and the inducements that were being offered for attendance 2. Final Guidance on Industry Supported Scientific and Educational Activities (Guidance only not regulation) a. Distinguish between educational activities that are independent from promotional influence b. Factors considered: i. Degree of control the company has over contents of program (selecting content, speakers) ii. Whether adequate disclosure during the program of sponsorship iii. Company's relationship to presenters iv. Whether unapproved uses will be discussed v. Whether the focus of the program is on educational content and free from commercial influence vi. Whether the audience was selected by company (i.e., reward for high prescribers dispensers or P&T decisionmakers) vii. Whether there are promotional activities such as presentations or exhibits in the meeting rooms. -Bad Ad program- FDA asks health care professionals to assist in recognizing misleading promotional activities and reporting them

Risk Evaluation and Mitigation Strategy (REMS)

-Intent- manage known or potential serious risks of the drug product -FDA can require REMS in pending NDA or mandate a REMS postmarket- i. when FDA believes it necessary to ensure the benefits of the drug outweigh the risk -Potential procedures required under REMS: i. Distribution of Medication Guides ii. Patient package insert iii. Communication plan aimed at health care professionals iv. ETASU- elements to assure safe use

Anti-Tampering Regulations

-Introduced tamper resistant packaging -FDA anti-tampering regulations require that: "cosmetic liquid or oral hygiene products" and vaginal products, contact lens solution, and most over the counter drugs be packaged in tamper-resistant packaging -Tamper-resistant packaging: packaging that has an "indicator or barrier to entry which if breached or missing can reasonably be expected to provide visible evidence to consumer that tampering has occurred

Promoting prescription drugs for off label use

-Off label- use for indications other than those approved by the FDA, and therefore not included in the labeling -FDAMA (§§ 551 and 552) relaxed FDA policy and allowed companies to provide written information about off label uses under certain circumstances to health care professionals and entities like PBMs, insurance plans, and group health plans. 1. Circumstances permitted: Company must have a. Filed an application for approval for the use b. Submit to the agency, 60 days before dissemination, of a copy of the information to be disseminated and any clinical trial information the company has c. Include with the disseminated information, a disclosure that the use has not been approved, a copy of the official labeling of the product, any other products or treatments that have been approved for use, the funding source for any studies relating to the use, and a bibliography of scientific publications regarding the use. -Current guidance allows companies to distribute unabridged peer review articles published in scientific/medical journals that have not been influence by the company. a. Should address well controlled clinical investigations considered by experts as scientifically sound. b. Should be accompanied by i. Approved labeling, ii. comprehensive bibliography of publications regarding the use, iii. representative publications (if available) that reach contrary or different conclusions, iv. distributed separately from promotional information, v. disclosure that the use has not been approved by FDA vi. disclosure of any relationship between the company and the article authors vii. disclosure of any known significant risks or safety concerns not addressed in the article.

Penalties of Misbranding and Adulteration

-Penalty- up to 1 year imprisionment, and/or $1,000 fine; second offense or intent to defraud or mislead- up to 3 years and $10,000 -Enforcement by FDA 1. Injunction- cause a violator to stop its illegal activity 2. Criminal proceedings- jail time and/or fines 3. Seize adulterated or misbranded food, drugs, cosmetics 4. Send warning letters 5. Corporate officer liability- officers can be convicted when their employees violate FDCA- without proof they acted intentionally or with negligence and even if they had no knowledge of the offense. 6. Product Recalls- FDA has authority or manufacturer can voluntarily recall; manufacturer responsible for contacting consumers. PHARMACIST responsible for knowing which drug products have been recalled. Pharm publications often list; available on FDA site: http://www.fda.gov/Drugs/drugsafety/DrugRecalls/default.htm a. Class I recall- reasonable probability that the product will cause serious, adverse health consequences or death b. Class II recall- product may cause temporary or medically reversible adverse health consequences, but the probability of serious adverse consequences is remote c. Class III recall- products not likely to cause adverse health consequences.

Abbreviated New Drug Application (ANDA)

-Process where generic products are approved following the expiration of a patent held by an innovator company. -Requires proof that the generic's pharmacokinetics, bioavailability, and clinical activity are similar to the innovator product

PMDA Amendment of 1992

-Requires companies to account for disposition of drug samples and prohibits reimportation of drugs exported to foreign countries. Samples or donated drug products generally can't be sold to consumers -"Pedigree" requirement-prescription drug wholesalers who are not the "authorized distributor of record" are required to provide a pedigree with each wholesale distribution of the drug. -Pedigree-statement of origin that identifies each prior sale, purchase or trade of the drug including the date of those transactions and the names and addresses of all parties to them. -Authorized distributor of record is a distributor that has an "ongoing relationship" with a manufacturer to distribute the manufacturer's product. Ongoing relationship=written agreement

Dietary Supplement Health and Education Act 1994

-defines dietary supplements and permits manufacturers to make certain claims that would otherwise be illegal under FDCA- this treats supplements more like food than drugs. -Dietary supplements (vitamins, herbs, and minerals) are exempt from FDCA food additive provisions. FDA has to demonstrate that these supplements are unsafe (rather than placing the burden on the manufacturer to demonstrate safety. -FDA established labeling requirements-permitted to use "nutritional support statements" describing the effect of the supplement -FDA issues good current manufacturing practice regulations for supplements. (cGMP)

Orphan Drug Act of 1983

-drugs intended to treat rare diseases and conditions may be designated "orphan drugs" -Tax and exclusive licensing incentives for manufacturers to develop and market drugs or biologics for treatment of rare diseases/conditions

Good Manufacturing Practices (GMP)

-set of regulations that establishes minimum requirements for the methods, facilities, or controls used in the manufacture, processing, packaging, or holding of a drug product. -Manufacturers must be registered with the FDA and are normally inspected EVERY 2 YEARS

Dietary Supplement

A dietary supplement is a product taken by mouth that is intended to supplement the diet and that contains one or more "dietary ingredients." The "dietary ingredients" in these products may include: -vitamins -minerals -herbs or other botanicals -amino acids -other substances found in the human diet, such as enzymes

Counterfeit drug

A drug, or the container or labeling, which WITHOUT AUTHORIZATION, BEARS THE TRADEMARK, TRADE NAME, OR OTHER IDENTIFYING MARK, imprint, or device, or any likeness OF A DRUG MANUFACTURER, PROCESSOR, PACKER, or DISTRIBUTOR, 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

Device: an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory -Device needs to be recognized in the official National Formulary or US Pharmacopoeia -Intended to diagnose or treat diseases

Adulteration

Drug is deemed adulterated if it is: a. Prepared packed or held in conditions where it may have been contaminated b. Exposed to a container that may have contaminated it c. Manufactured under conditions that do not conform to current good manufacturing practices (GMP) d. Drug is adulterated if its strength, quality, or purity differs from those on the label or from compendia standards if its subject to compendia

Durham-Humphrey Amendment 1951

Established 2 drug classes: prescription and over the counter. Prescription drugs were required to contain a warning that the drugs could be dispensed legally only with the authorization of a health professional ("Caution: Federal law prohibits dispensing without a prescription"). Also authorized oral prescriptions and refills of prescription drugs.

Prescription Drug Marketing Act of 1987

Establishes sales restrictions and recordkeeping requirements for prescription drug samples and prohibits hospitals and health care entities from reselling their pharmaceutical purchases to other businesses and requires state licensing of drug wholesalers.

Medical Device Amendment of 1976

Gave FDA more oversight of medical devices. -Classified/categorized devices according to function and risk. -Medical devices were required to meet certain performance standards. -Pre-market approval required. -Conformance to good manufacturing practices -Adherence to record keeping and reporting of adverse events.

Elements to assure safe use (ETASU)

May require that 1. health care providers have special training or experience 2. drug may only be dispensed in specific settings 3. and/or that the patient enroll in a registry and agree to testing and monitoring

Phase 4 study and Post Marketing Surveillance

Post market surveillance-once a NDA has been approved, manufacturer may distribute drug in interstate commerce a. Must maintain and establish postmarketing records and reports. Must submit reports of: i. any serious adverse reactions 21 C.F.R. §314.80 ii. any new information relating to the drug's safety and efficacy 21 C.F.R. §314.81 -Including information about current clinical studies, quantity of drug distributed, labeling, and advertising. Phase IV studies-manufacturers engage in postmarket clinical studies a. Determine new uses or abuses for a drug b. Obtain additional safety or efficacy data for labeled indications c. FDAAA- Congress granted FDA agency authority to require phase IV- can require for any prescription drug

New Pregnancy/Lactation Labeling

Pregnancy guidance: -Pregnancy exposure registry-if a registry is established for drug -Risk summary-statements that describe the risk of adverse developmental outcomes based on relevant human, animal data and drug's pharmacology -Clinical considerations: a. Disease associated maternal or embryo/fetal risk b. Dose adjustment during pregnancy and post-partum c. Maternal adverse reactions d. Fetal/neonate adverse reactions e. Labor or delivery - Data-from human and animal studies

Drug Efficacy study implementation (DESI)

Program implemented in response to Kefauver-Harris Amendment requiring drugs be effective as well as safe FDA commissioned National Academy of Sciences National Research Council to study the drugs and submit recommendations. Council categorized all reviewed drugs into one of six categories 1. Effective 2. Probably effective (additional evidence needed) 3. Possibly effective (little evidence submitted) 4. Ineffective (no acceptable evidence 5. Effective, but (effective but better, safer, or more conveniently administered drugs available) 6. Ineffective as a fixed combination

Federal Food Drug and Cosmetic Act 1938

Required manufacturers to demonstrate safety of new drugs prior to marketing. Labels must contain directions for use and warnings of habit-forming properties of certain drugs. This also applied to devices and cosmetics.

Kefauver-Harris Amendment 1962

Required that drugs be proved not only safe, but effective. Added more extensive controls for clinical investigations by requiring informed consent of research subjects and reporting of adverse drug reactions. Drug advertising would have to include accurate information about side effects. Established good manufacturing practices and mandated regular inspections of production facilities.

Prescription Labeling Requirements

The principal display panel (PDP) is the panel of a label that is most likely to be displayed, presented, shown, or examined by the end user. FDA recommends that the PDP include the following critical information: -Name, logo, and place of business of manufacturer, packer or distributor -NDC number -Proprietary name, established name or proper name -Generic name -Ingredient information, including quantity and proportion of each active ingredient; names of inactive ingredients -Quantity in terms of weight or measure (e.g., 100mg) -Net quantity of the container (e.g.,100 tablets) -Recommended or usual dosage or reference to package insert -Route(s) of administration -Warnings (if any) or cautionary statements (if any) -Rx-only statement (legend) -expiration date-if listed in only month and year, it means the last day of the indicated month. -Statement specifying type of container to be used in dispensing -Bar code/control number/lot number

Food

The term "food"means: (1) articles used for food or drink for man or other animals, (2) chewing gum, and (3) articles used for components of any such article.

Drug

The term drug means: -Articles recognized in the official USP/NF or Homeopathic Pharmacopoeia, or any supplement to any of them; and -Articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man or other animals; and -Articles other than food intended to affect the structure or function of the body of man or other animals

FDCA Prohibited Acts

Two major prohibitions: misbranding and adulteration 1. Strict liability- liable regardless of intention or knowledge 2. 21 U.S.C. §301(i)(3) illegal for pharmacist to make, dispense, or hold for dispensing a counterfeit drug- this includes dispensing a placebo or dispensing a drug labeled as another drug 3. 21 U.S.C. §301(k)- for pharmacists who re-package or relabel drugs, either prescription or OTC, the new label must confirm to FDA specifications, or constitutes misbranding. 4. Specific prohibitions: a. Adulteration or misbranding of food, drugs, device or cosmetic i. Introduction, delivery, sale, receipt, or offer of delivery b. Refusal to permit access to or copying of records as required or the failure to establish or maintain records or reports c. Refusal to permit entry or inspection d. To manufacture food, drug, device, or cosmetic that is adulterated or misbranded. e. Doing any act that causes a drug to be a counterfeit drug, or the sale or dispensing, or the holding for sale or dispensing of a counterfeit drug f. Altering, mutilating, destroying, obliterating, removing, the whole or part of the labeling of a food, drug, device or cosmetic, if done during the sale (whether or not the first sale) after shipment in interstate commerce and results in the article being adulterated or misbranded. g. Introducing or delivering into interstate commerce, a dietary supplement that is unsafe under section 413.

Misbranding

What is misbranded: a. False or misleading labeling b. Labels lacking: NAME and PLACE of business of the manufacturer, packer or distributor, and ACCURATE statement of the QUANTITY of the contents in terms of weight, measure, or numerical count. c. Labels of drug lacking: name of drug, the name and quantity (or if determined appropriate, the proportion of each active ingredient, and the established name of each inactive ingredient listed in alphabetical order on the outside container of the retail package for OTC d. Lacking: adequate directions for use -Imitation drugs are considered misbranded

Label

a display of written printed or graphic matter on the product's container and on the outside container or wrapper, if any.

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 that term shall not include soap.

Which agencies are responsible for drug advertising?

i. FDA- regulates prescription drug advertising under the FDCA (15 U.S.C. § 352(n) ii. Federal Trade Commission (in collaboration with FDA) regulates nonprescription drugs under the Federal Trade Commission Act (15 U.S.C.§ 45)

Items in Package Insert

i. Highlights of Prescribing Information 1. Product Names, Other Required Information 2. Boxed Warning a. When use of drug may lead to death or serious injury, the FDA may require the warning of the special problem in a prominently displayed box 3. Recent Major Changes 4. Indications and Usage 5. Dosage and Administration 6. Dosage Forms and Strengths 7. Contraindications 8. Warnings and Precautions 9. Adverse Reactions 10. Drug Interactions 11. Use in Specific Populations ii. Full Prescribing Information: Contents iii. Full Prescribing Information: Boxed Warning 1 Indications and Usage 2 Dosage and Administration 3 Dosage Forms and Strengths 4 Contraindications 5 Warnings and Precautions 6 Adverse Reactions 7 Drug Interactions 8 Use in Specific Populations 9 Drug Abuse and Dependence 10 Overdosage 11 Description 12 Clinical Pharmacology 13 Nonclinical Toxicology 14 Clinical Studies 15 References 16 How Supplied/Storage and Handling 17 Patient Counseling Information

Pure Food and Drug Act 1906

prohibited marketing of adulterated (contaminated) and misbranded food and drugs. Law only made sure that product was correctly identified. Law didn't limit the claims that a manufacture could make and law didn't require pre-market approval.

Prescription Drug User Fee Act 1992

requires manufacturers seeking new drug approval to pay fees for applications and supplements when the FDA must review clinical studies.

Drug Price Competition and Patent Term Restoration Act of 1984

streamlined generic drug approval process while giving patent extensions, in certain cases, to innovator drugs. Intent-make generics more available, and incentivize development of new drugs