Pharmacy Practice and the Law Exam 1

Sulfanilamide Elixir Tragedy of 1937

-An anti-infective sulfa drug that used diethylene glycol as solvent → however, no toxicity tests had been done and the solvent was a deadly poison -Caused 107 deaths -FDA had to remove the product on the basis of a technical misbranding violation (elixir must contain alcohol but the product did not) as the FDA did not have the authority to ban unsafe drugs

Standing Advisory Committees

-Composed of physicians, nurses, pharmacists, statisticians, epidemiologists, and other professions recruited through the Federal Register and often are nominated by professional organizations and professional schools -The secretary of DHHS makes the final selection of members from the list of nominees -Committee size ranges from 9 -15 members -FDA is not obligated to follow a committee recommendation, but it often does

Food and Drug Administration (FDA)

-FDA is a component of the Department of Health and Human Services (DHHS) → administrating authority of the FDCA is really vested with the secretary of DHHS -President appoints the commissioner of the FDA with confirmation of the Senate (commissioner is still accountable to the secretary)

Nutraceuticals and Functional Foods

-Nutraceuticals: foods that provide health and medical benefits, including the prevention and treatment of disease -Functional foods: fortified or enhanced, often with a dietary supplement, such as drinks with ginseng or kava kava added and foods fortified with calcium or probiotics

United States v. Johnson (1911)

-The manufacturer claimed on the label that the drug was effective against cancer, knowing that this representation was false → Court ruled that the misbranding provision in the law prevented false statements only as to the drug's identity (strength, quality, purity) = did not prevent false or misleading efficacy claims

Switch of Prescription Drugs to OTC by:

1) The manufacturer may request the switch by submitting a supplemental application to its approved NDA 2) The manufacturer may petition the FDA 3) The FDA may add or amend an OTC monograph

Adequate Information for Use

For prescription drugs, labeling must include: → The drug's indications → Side effects → Dosages → Routes, methods, frequency, an duration of administration → Contraindications → Other warnings and precautions that enable a practitioner to administer, prescribe, or dispense the drug safety

Schlieter v. Carlos (1989)

→ An inpatient contended that the hospital was negligent in not providing her with a PPI when she was given estrogen (Premarin) but the defendant hospital argued that it had a right to rely on the treating physician to provide the PPI if the physician so wished → Court disagreed establishing that an institution cannot delegate its responsibility for providing a PPI to the prescribing physician → intent of the regulation is that patients, not physicians, must be given the information

Dietary Supplement Health and Education Act of 1994 (DSHEA)

→ Defines dietary supplements and permit manufacturers to make certain claims that otherwise would have been illegal under the FDCA → forced the FDA to regulate dietary supplements more as foods than as drugs -Created the category of dietary supplements and significantly altering the FDA's authority to regulate dietary supplements (FDA cannot require premarket approval or withdrawal → must prove that it is unsafe to do anything) → Dietary supplement: a product that is intended for ingestion, is intended to supplement the diet, and 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

Institutional Review Board (IRB)

→ For any clinical trial, requires that potential participants know the risks, possible benefits, and alternative courses of treatment (informed consent) → IRB must approve the study and is designated by the institution charged with reviewing any research projects involving human subjects

Current Good Manufacturing Practices (CGMP) for DSHEA (2007)

→ In response to critic concerns of DSHEA (1. unsafe and FDA had limited power to act aggressively and protect the public, 2. lack of consumer information of drug interactions and dietary supplements, and 3. lack quality standards for strength and purity), now requires manufacturers to comply with current good manufacturing practices → Require manufacturers to evaluate the identity, purity, quality, strength, and composition of their products → if product contains contaminants or lacks the ingredient, this would be adulterated or misbranded

Special Dietary Foods

→ Includes but are not limited to foods that supply a special dietary need that exists by reason of a physical, physiological, pathological, or other condition such as the condition of disease, convalescence (recovery), pregnancy, lactation, infancy, allergic hypersensitivity to food, underweight, overweight, or the need to control the intake of sodium -Examples: infant formulas, artificial sweeteners, caloric supplements

Drugs versus Devices Factors

→ Is the product intended to deliver drugs to the patient, but is not pre filled by the manufacturer (ex. an empty implantable infusion pump)? → Is the drug component included solely to make the product safer (ex. a surgical drape impregnated with antimicrobial agents)? → Is the drug component intended to have a therapeutic effect (ex. an intrauterine contraceptive device that releases a hormone)?

Amended Pure Food and Drug Act of 1912

→ Prohibited false and fraudulent efficacy claims -Was difficult to enforce because it required the government to prove fraudulent intent on the part of one who made false statements on the label as by pleading ignorance, violators could escape enforcement

Safe Medical Devices Act of 1990

→ Strengthened the Medical Devices Amendment Act of 1976 by giving the FDA additional authority especially related to post marketing requirements and premarket notification and approval, while expediting the premarket device approval process → Requires device-user facilities and distributors to report to the Secretary of Health and Human Services any death, serious injury, or serious illness that may be related to the product (device-user facility: "a hospital, ambulatory surgical facility, nursing home, or outpatient treatment facility that is not a physician's office" → Subsequently FDAMA removed the requirement that distributors must submit adverse reports to the FDA or to device manufacturers → must maintain records of adverse events

Labeling Requirements under the Durham-Humphrey Amendment

→ Subsection (b)(2) recognizes that some of the information mandated by section 502 (manufacturer labeling) would be impractical for drugs dispensed pursuant to prescription and should fall under the discretion of the health care provider: -The label must not be false or misleading -The drug dispensed must not be an imitation drug -The drug must not be sold under the name of another drug -The packaging and labeling must conform to official compendia standards -If it is a drug liable to deterioration, it must be packaged and labeled appropriately -It must be packaged in conformance with the Poison Prevention Packaging Act → Does not give complete discretion to health care providers to the exclusion of the government (health care providers should still distribute written information to patients for certain prescription drugs) → Must also include: name, initials, or license number of dispensing pharmacist; the expiration date of the drug if any; drug's name and strength; address of the patient; name of the manufacturer or distributor; lot or control number

Pedigree

→ The Prescription Drug Marketing Act (PDMA) granted the FDA the authority to require wholesalers that are not manufacturers and that are not authorized by a manufacturer of the drug to maintain a record that identifies each prior sale, purchase, or trade of the drugs since they receive and distribute → Contains information on each transaction changing the ownership of the drug → Pedigrees are made possible by Radio Frequency Identification (RFID) technology, which allows drug product packages to be tagged with tiny chips containing an electronic product code or unique electronic serial number (history of a drug can be traced from the manufacturer to the final dispenser) → SNI = standardized numerical identifiers → sNDC = serialized National Drug Code = doesn't exist anymore

United States v. Baxter Healthcare Corporation (1990)

→ The court considered whether reconstituting, repackaging, freezing, and distributing approved antibiotic drugs make them new drugs → Baxter argued that it simply prepared the drugs according to the label instructions exactly as a physician or pharmacist would and, thus, the drugs could not be new drugs → The court found that the reconstitution did indeed make the drugs new drugs because the procedure raised concerns about the safety and efficacy of the final product → Court referred to the statute and regulations that require a full description of the methods, facilities, and controls used in manufacturing, processing, and packaging with the submission of an NDA

Definition of "New Drugs"

→ The drug contains a new substance (ex. active ingredient, excipient, carrier, 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

Houck v. Iowa Bd. of Pharmacy Examiners (2008)

→ The pharmacist compounded a nasal spray using several nonprescription drug ingredients and the product worsened the patient's condition → Patient filed a complaint with the Iowa Board of Pharmacy and found the pharmacist had unlawfully manufactured and dispensed a compounded drug without a prescription and the court upheld the Board's interpretation that OTC compounded drugs require a prescription

FDA's Evaluation of Health Claims: UnQualified and Qualified

→ Unqualified health claims: allowed if authorized by the agency pursuant to the significant scientific agreement test → Qualified health claims: when the claim does not meet the significant scientific agreement test and the claim would be misleading without the qualification - when there is more evidence for the claim than against it and must be truthful and not misleading and appropriately indicate the level of scientific support

Definition of Prescription Drugs

→ Unsafe for use except under the supervision of a practitioner because of the toxicity, the method of use, or the collateral measures necessary to use the drug → Subject to the new drug application (NDA) approval process

Medical Device Amendments of 1976

→ Used to classify devices as drugs when deemed appropriate and necessary and prompted by public safety concerns with certain devices → Classification of devices according to their function → Premarket approval → Establishment of performance standards → Conformance with GMP regulations → Adherence to record and reporting requirements

FDAMA's Compounding Provisions

(1) The first requirement stated that the prescription could not be solicited (2) The second offending requirement provided that pharmacies and physicians could promote and advertise that they compound, but that they could not advertise or promote the compounding of any particular drug, class of drug, or type of drug → Supreme Court found these two requirements unconstitutional because they amounted to an impermissible regulation of commercial speech under the First Amendment → INVALIDATED

Action on Smoking and Health v. Harris (1980) Food and Drug Admin. v. Brown & Williamson Tobacco Corp (2000) Sottera, Inc. v. Food & Drug Administration (2010)

-Public interest group wanted cigarettes declared as drugs since they contain nicotine → FDA determined that based on drug definition, cigarettes were not considered a drug because no therapeutic claims were made and the court agreed -1990:FDA changed its position to say that nicotine is a drug and that cigarettes and smokeless tobacco are drug-delivery systems since they are intended to satisfy addiction, stimulation and tranquilization, and weight control -1996: FDA intended to reduce tobacco consumption but tobacco companies challenged the FDA by arguing that the agency lacks authority to regulate tobacco products → court agreed with plaintiffs -2009: Congress enacts the Family Smoking Prevention and Tobacco Act granting the FDA authority to regulate tobacco products → FDA can regulate the contents of tobacco products, require disclosure of product contents, prohibit certain additives, require more effective warnings, and strictly control or prohibit marketing sales campaigns -2008-2010: FDA determined that electronic cigarettes were unapproved drug/device combination products → manufacturers challenged the FDA's assertion and the US Court of Appeals for the DC Circuit found for the manufacturers on the basis that the agency can regulate the products under the 2009 Tobacco Act and that they are not drugs or devices unless marketed for therapeutic purposes

Park Doctrine: United States v. Dotterweich (1943) and United States v. Park (1975)

1) The president of a repackaging and relabeling company was convicted of adulteration and misbranding even though there was no evidence that he knew of the wrongful acts → Court's rationale was that it is better to place the burden on those in a position to discover the violations than on an innocent and helpless public 2) → The president of a nationwide grocery chain was charged with holding food products under unsanitary conditions and contended that he delegated the responsibility for sanitation to employees and could not be expected to oversee all corporate operations personally → Court acknowledged defense, but asked defendant to prove this → Found president liable under the FDCA → Act imposes a duty not only seek out and correct violations but also to implement procedures to ensure that violations will not occur → Established that corporate officials can be personally prosecuted without proof they acted internally or with negligence and even if they had no knowledge of the offense

DSHEA Permitted Structure/Function Statements

1. Statements that the product will benefit a classical nutrient deficiency disease as long as it also discloses the prevalence of the disease in the United States 2. Statements that describe the role of the dietary supplement in affecting the structure or function of the body 3. Statements that characterize the documented mechanism by which a nutrient or dietary supplements acts to maintain structure or function 4. Statements describing the general well-being from consumption of a nutrient or dietary ingredient (ex. energizer, relaxant, muscle enhancement) → Label of product must contain the disclaimer: "This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease." → Manufacturer must notify the FDA within 30 days if it makes one of the permitted statements

Ephedrine Alkaloid Dietary Supplements (EDS)

Banned in 2004 because adverse event reports and 133000 pages of scientific data, expert reviews, comments, and other materials found EDS unsafe → Although EDS is promoted to achieve weight loss, enhance athletic performance, and increase energy, its effects are temporary, modest, and generally do not improve health → also found that EDS increases risk of serious adverse events including heart attacks, strokes, and deaths

FDA Drug Rating and Classification System

Chemical Types: 1. The active moiety is a new molecular entity 2. The active moiety is in a new salt or ester form 3. The dosage form or formulation is new 4. The product is a new combination of compounds 5. The drug product is essentially a duplicate of another drug product 6. The drug is a product previously marketed by the same firm (usually for new indications) Therapeutic Potential: letters P and S → P = priority indicates that the drug may represent a therapeutic advance for one or more of these reasons: (1) no other effective drugs are available, (2) it is more effective or safe than drugs currently used, (3) it as important advantages such as greater convenience, reduced side effects, or improved tolerance or usefulness in special populations → S = standard means that the drug may have therapeutic properties similar to those of drugs already on the market and offers at best only minor improvements over existing drug therapies

Guidance Documents

Clarify laws or regulations, to explain how compliance with the laws or regulations may be achieved, and to outline review and enforcement approaches

United States v. Undetermined Quantities of an Article of Drug Labeled as Exachol (1989)

Exachol manufacturers distributed literature proclaiming that the product was useful in the prevention and treatment of coronary disease → based on claims, FDA wanted to label this as a drug, but the manufacturers argued that the product was a special dietary food and not a drug → court found that the FDA permitted some foods to be labeled with appropriate health-related messages and health claims so could not single out Exachol as a drug while failing to take action against other such products

National Nutritional Foods Association v. Mathews (1977)

FDA was unsuccessful in its attempt to classify vitamins A and D in high dosages as drugs on the basis of a lack of nutritional value and potential toxicity → court held that nutritional value and toxicity were not relevant to the statutory definition of a drug

Medical Foods

Formulated for oral use under the supervision of a physician and that are intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements are established by medical evaluation -Examples: foods formulated without the amino acid phenylalanine for phenylketouria, folic acid, B6, B12 combination products for hyperhomocysteinemia

FDA 2002 Compliance Policy Guide (CPG)

In determining if to initiate an enforcement action against a pharmacy, the FDA will consider if the pharmacy engages in any of the following nine acts: 1) Compounding in anticipation of receiving prescriptions, except in very limited quantities 2) Compounding drugs withdrawn or removed from the market for safety reasons 3) Compounding from bulk ingredients not approved by the FDA 4) Receiving, storing, or using drugs without first obtaining written assurance from the supplier that each lot of the drug was made in an FDA-registered facility 5) Receiving, storing, or using drug components not guaranteed or determined to meet compendia requirements 6) Using commercial-scale manufacturing or testing equipment 7) Compounding for third parties for resale 8) Compounding drugs that are commercially available or that are essentially copies of commercially available products 9) Failing to operate in conformance with applicable state law

Current Good Manufacturing Practices (CGMP)

Inspections are designed to: → Confirm that the production and control procedures result in the proper identity, strength, quality, and purity of drugs → Identify deficiencies → Ensure correction of the deficiencies

Nutrilab, Inc., et al. v. Schweiker (1983)

Involved a weight-reduction product, a starch blocker, and whether it was a food or drug → plaintiffs argued that the product was a food because it was derived from kidney beans however, the court disagreed, finding for the FDA on the basis that the product neither fit the statutory definition of food nor the commonsense definition of food, in that people use food primarily for taste, aroma, or nutritive value -Led to classifications of food versus drugs and special dietary foods and medical foods

United states v. An Article...Consisting of 216 Cartoned Bottles, More or Less (1969)

Manufacturer distributed a lotion composed of bovine albumin and distilled water → When applied to skin and allowed to dry, the lotion left a film that tightened the skin, thus temporarily masking imperfections and making the skin look smoother → Claimed that the lion would "lift out puffs" or give a "facelift without surgery" → Court applied the standard of what an "ignorant, unthinking, and credulous" consumer would believe not what a reasonable consumer would believe so considered the lotion a drug unless this claim was taken off

Investigational New Drug (IND) Application

Must include a substantial amount of information including: -The name of the drug -Its composition -Methods of manufacture and quality control -Information from preclinical (animal) investigations regarding pharmacological, pharmacokinetic, and toxicological evaluations -Include information about the experience and qualifications of the clinical investigators, as well as a complete outline of the proposed clinical trials

Adequate Directions for Use

Must include in addition to purposes and conditions of use: → 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 )in relation to meals, onset of symptoms, or other factors) → The route or method of administration or application → The preparation necessary for use (Ex. shaking, dilution)

Patient Protection and Affordable Care Act of 2010 (PPACA/ACA)

Provided sweeping changes through the entire health care system

Prescription Drug User Fee Act of 1992 (PDUFA)

Requires manufacturers seeking NDAs to pay fees for applications and supplements when the FDA must review clinical studies → provide FDA with the resources to hire more reviewers to assess these clinical studies and speed up the NDA reviews - Must be reauthorized every 5 years

Secondary Wholesalers

Wholesalers not authorized by a manufacturer and usually far outnumber authorized wholesalers

"Mandatory" vs. "Permissive Substitutions (Drug Product Selection Law)

→ "Mandatory" substitutions: pharmacists must substitute a less expensive generic drug for the brand-name drug unless the prescriber writes "dispense as written", "brand necessary", or a similar notation on the prescription → "Permissive" substitution: a pharmacist may choose to substitute if the prescriber issues the prescription in a way that permits substitution → Without the prescriber's permission, either express or tacit, substitution is not allowed in most states, even if the consumer wishes a substitute

Supplemental New Drug Applications

→ "Prior approval" supplement: agency must approve the change before the sponsor can implement it -For changes in any part of the production, ranging from the synthesis of the drug, to the manufacturing processes of the drug, to most of the labeling of the drug →"Change Being Effected (CBE)" supplement: allows the sponsor to implement the change before the FDA approves it -For certain types of labeling changes such as those that strengthen warnings or dosage and administration information, or for certain changes in manufacturing methods, facilities, and controls -Labeling changes must reflect "newly acquired information" → Reported in the annual report: for very minor changes, such as editorial changes in labeling or changes in container size

Hoffman LaRoche, Inc. v. Weinberger (1975)

→ A US district court held that the FDA could not allow drugs to be marketed unless their ANDAs or NDAs had been approved

Noesen v. State, Dept. of Regulation and Licensing (2008)

→ A Wisconsin pharmacist informed the employer of his conscientious objection to dispense birth control prescriptions, but did not tell the employer that he would not transfer refills upon the request of another pharmacy → When a patient attempted to refill her birth control prescription, the pharmacist told her he could not dispense it and that there was no other pharmacist on duty so the patient went to another pharmacy, but the pharmacist refused to transfer the prescription to the other pharmacy resulting in the patient missing a dose → State Board of Pharmacy found the pharmacist guilty of unprofessional conduct because his failure to transfer the prescription constituted a danger to the health and safety of the patient and substantially departed from the standard of care of a pharmacist → The Board ordered that the pharmacist inform all future employers in writing that he would not dispense birth control prescriptions and outline the step he would take to ensure that a patient has access to the medication

Medical Center Pharmacy v. Gonzales (2006) Medical Center Pharmacy v. Mukasey (2008)

→ A group of 10 compounding pharmacies brought legal action against the FDA seeking declarative and injunctive relief from the FDA's policy of considering lawfully compounded drugs as new drugs → The court agreed with the plaintiffs, finding that the non advertising provisions are severable, thus leaving FDAMA in effect and also held that compounded drugs created for an individual patient pursuant to a prescription are "implicitly exempt from the new drug definitions..." → The basis for the court's conclusion was that FDAMA's provisions stating that compounded drugs are not new drugs remains effective and demonstrates the intent of Congress → Court agreed that the non advertising provisions were severable but held that pharmacy compounded drugs are new drugs but "are neither uniformly exempt from the new drug approval requirements nor uniformly subject to them" → court held that compounded drugs are exempt provided the pharmacy meets all the conditions established in FDAMA → FDA is prohibited from treating compounded drugs as new drugs in Louisiana, Mississippi, and Texas, but can treat compounded drugs as new drugs in the rest of the country

Sentinel Initiative

→ A proactive surveillance system designed to detect early signs of medication risk and safety problems

Dietary Supplement and Nonprescription Drug Consumer Protection Act (2006)

→ Adds serious adverse events reporting systems: (1) nonprescription drugs and (2) dietary supplements → Must report any serious adverse event within 15 business days and must submit any subsequent medical information received within 1 year of the initial reported event → Product labeling must include either the supplier's domestic address or a continuously operating toll-free telephone number so consumers can report serious adverse events → Suppliers must maintain records related to each report for 6 years and allow inspection of the record

Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council, Inc. (1976)

→ Allows pharmacists to advertise prescription drug prices as to prohibit would violate the First Amendment protection of free speech → 2 issues: 1) Does the 1st Amendment right of free speech apply to the listeners or recipients of the speech? Court: "If there is a right to advertise, there is a reciprocal right to receive the advertising and it may be asserted by these appellees 2) Does the 1st Amendment apply to commercial speech? Court: even if an advertiser's interest is purely economic, the advertiser does not lose First Amendment protection → Court rejected all the state pharmacy board's reasons for the advertising ban and replied that the state appeared to be protecting its citizens by keeping them ignorant → Does not bar a state from making it illegal for pharmacists to offer discounts or rebates in connection with the sale of drugs

Medicare Prescription Drug, Improvement and Modernization Act (MMA)

→ Allows the Secretary of Health and Human Services (HHS) to promulgate regulations that facilitate the wholesale importation of prescription medications from Canada → Can only do so if the secretary can certify the program would pose no additional risk to public health or safety and would significantly reduce cost → None have been recognized for certification to date

"Paper" New Drug Applications

→ Although the FDA would accept ANDAs for generic drug equivalents marketed between 1938 and 1962, it did not accept ANDAs for generic equivalents marketed after 1962 → A generic drug manufacturer would not have to duplicate the actual research establishing the safety and efficacy of the innovator drug, as a full NDA would require and would just submit evidence of its drug's safety and efficacy on the basis of the published scientific data generated from the innovator manufacturer's studies

Generic Drug Enforcement Act of 1992

→ Authorizes the 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

Wedgewood Village Pharmacy Inc. v. U.S. (2005)

→ Based upon a number of concerns regarding a pharmacy compounding drugs that were essentially copies of commercially available products, the FDA obtained a warrant and commenced inspection → However, the pharmacy insisted that the FDCA specifically excludes pharmacies from FDA inspection if they do not manufacture or compound drugs or devices other than in the regular course of business → Court stated that Congress intended that the FDA must be granted the authority to generally inspect pharmacies in order to determine if the exemption applies otherwise the FDA would have to rely on the representations of the pharmacies and are essentially powerless to enforce the law → Court found that the law prohibits the FDA from inspecting the records of the pharmacy unless the general inspection reveals that the pharmacy is manufacturing and thus does not qualify for the exemption

Food and Drug Administration Modernization Act of 1997 (FDAMA)

→ Builds on the Prescription Drug User Fee Act (PDUFA) to require FDA mission statement defining the scope of its responsibilities, and requires the agency to publish a compliance plan in consultation with industry representatives, scientific experts, health care professionals, and consumers = eliminate backlogs in the approval process and ensure the timely review of applications → Creates a fast-track approval process for drugs intended for serious or life-threatening diseases, establishes a databank of information on clinical trials, authorizes scientific panels to review clinical investigations, and expands the rights of manufacturers to disseminate unlabeled use information → Expands FDA's authority over over-the-counter (OTC) drugs and establishes ingredient-labeling requirements for inactive ingredients → Mandates priority review for breakthrough technologies in medical devices and allowing the FDA to contract with outside scientific experts for review of medical device applications

CVS Pharmacy Wayne case

→ CVS Pharmacy Wayne case and its 1-week special price of $3.00 for prescription drugs → Found guilty of unprofessional conduct for violating a New Jersey law that prohibited the distribution of discounts, premiums, or rebates, except to those more than 62 years of age → The court sustained the validity of the law

Kefauver-Harris Amendment of 1962 (Drug-Efficacy Amendment)

→ Came about because of incident with Thalidomide was confirmed in 1961 to cause birth defect of phocomelia (seal limbs) in thousands on infants → Required that drugs not only be proved safe, but also effective (included all drugs marketed between 1938-1962) → Transferred jurisdiction of prescription drug advertising from the Federal Trade Commission (FTC) to the FDA → Established the Good Manufacturing Practices (GMP) requirements → Added more extensive controls for clinical investigations by requiring the informed consent of research subjects and reporting of adverse drug reactions

Product Recall Classes

→ Class I: issued when there is a reasonable probability that the product will cause serious, adverse health consequences or death → Class II: when the product may cause temporary or medically reversible adverse health consequences, but the probability of serious adverse consequences is remote → Class III: products that are not likely to cause adverse health consequences -Guidelines issues by the FDA and recalls sent by first-class mail with the envelope and letterhead conspicuously marked, preferably in red, with URGENT: DRUG RECALL

U.S. v. Bader (2009)

→ Colorado pharmacy imported HGH and dispensed prescriptions in this manner - pharmacist imported HGH from another country representing that it was for compounding so FDA inspectors allowed the drug into the country as an "Active Pharmaceutical Ingredient (API)" - if the drug was to be sold as a finished drug, it could not be imported → FDA contended that the pharmacist made false representations since it did not compound the HGH but sold it as a finished drug and charged him with conspiracy to facilitate the sale of smuggled goods → Federal district court, based on Colorado's definition of compounding, which includes repackaging as compounding, found that the pharmacy was compounding → However, at trial, the government would most likely establish that the pharmacy violated FDAMA or the compliance guide (ex. compounding a copy of a commercially available product or using an unapproved active ingredient) that would make the compounded product as new drugs

Food Additives Amendment of 1958

→ Components added to food products must receive premarket approval for safety → Delaney Clause: prohibits the approval of any food additive that might cause cancer

United States v. Article of Drug - Decholin (1967)

→ Court established that the FDA must prove two issues to change the status of a drug from OTC to prescription: (1) That the toxicity and method of use require practitioner supervision (2) That the collateral measures necessary to use the drug require supervision

Poison Prevention Packaging Act (PPPA) of 1970

→ Created with the intent of protecting children from accidental poisonings with household substances → Household substance is defined as: -A hazardous substance in the federal Hazardous Substances Act -An economic poison under the federal Insecticide, Fungicide and Rodenticide Act -A food, drug, or cosmetic under the FDCA -A household fuel when stored in a portable container → Now the responsibility of the Consumer Product Safety Commission (CPSC) → Containers must be manufactured such that 80% of children <5 years of age cannot open them, but 90% of adults can

Homeopathic Pharmacopoeia of the United States (HPUS)

→ Defines homeopathy as the "art and science of healing the sick by using substances capable of causing the same symptoms, syndromes, and conditions when administered to healthy people" → Established by the Homeopathic Pharmacopoeia Convention of the United States (HPCUS) → Private, nonprofit organization of scientific experts in homeopathy → HPUS Revision Service = a loose-leaf binder publication that allows for continual revisions

National Drug Code Number

→ Drug products are identified and reported using a unique, 11-digit, 3-segment number → The first segment of the code is assigned by the FDA and identifies the manufacturer or distributor → The second segment identifies a specific strength, dosage form, and formulation for a particular firm → The third segment identifies package size and type of drug

FDA 1992 Compliance Policy Guide

→ Emphasized that the FDA had no intention of regulating pharmacy's historic exemption to compound drugs extemporaneously in reasonable quantities pursuant to prescription → Also states that pharmacists may prepare "very limited quantities" of drugs before receiving valid prescriptions, provided that these anticipated quantities can be documented historically with prescriptions on file → However, the FDA stated something many compounding pharmacists believed set the tone for how the agency felt about pharmacist compounding and felt that the FDA's enforcement activities were too intrusive → Congress agreed and somewhat reduced the FDA's authority over drugs compounded in pharmacies in FDAMA

Durham-Humphrey Amendment of 1951 (Prescription Drug 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" and this requirement would be satisfied with inclusion on the label of directions from the prescriber → Authorizes oral prescriptions and refills of prescription drugs

Durham-Humphrey Amendment of 1951 (Prescription Drug Amendment) - Review

→ 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" and this requirement would be satisfied with inclusion on the label of directions from the prescriber → Authorizes oral prescriptions and refills of prescription drugs

Prescription Drug Marketing Act of 1987

→ Establishes sales restrictions and record keeping requirements for prescription drug samples → Prohibits hospitals and other heath care entities from reselling their pharmaceutical purchases to other businesses and requires the state licensing of drug wholesalers

Prescription Drug Marketing Act of 1987 (PDMA) - Review

→ Establishes sales restrictions and record keeping requirements for prescription drug samples → Prohibits hospitals and other heath care entities from reselling their pharmaceutical purchases to other businesses and requires the state licensing of drug wholesalers ADDITIONALLY: → Require states to license wholesale distributors of prescription drugs → Ban the reimportation of prescription drugs, except by the manufacturer or for emergency use → Ban the sale, trade, or purchase of drug samples → Mandate storage, handling, and record keeping requirements for drug samples → Ban the trafficking in or counterfeiting of drug coupons → Prohibit the resale of prescription drugs purchased by hospitals or health care facilities, with certain exceptions → Violation of PDMA includes 10 years in prison, a $250,000 fine, or both for first offenses

U.S. v. Franck's Lab, Inc. (2011)

→ FDA contended that any medications compounded for animals from bulk substances, even pursuant to a prescription from a veterinarian, are new drugs and violate the FDCA → Court noted that the FDA seeks to eradicate the line between manufacturing and traditional pharmacy compounding contrary to congressional intent → The agency lacks the statutory authority to regulate the traditional pharmacy compounding of animal drugs

Department of Homeland Security Appropriations Act of 2007

→ FDA has permitted the personal importation of small amounts of drugs, but only if they are approved in the United States and are used for the treatment of a serious condition for which no satisfactory treatment is available in this country → The drug must not represent an unreasonable risk and the patient seeking to import the drug must provide the name of the licensed US physician responsible for treating the patient with the unapproved drug → An individual may import an FDA-approved prescription drug from Canada and applies only to individuals transporting the drug on their person in a quantity not to exceed a 90-day supply → The drug may not be a controlled substance or biological product → Only allows for a total combined quantity of 50 dosage units that must be transported personally (not shipped) across the border → The drug must be in the original, dispensed container and must be declared to Customs

United States v. Article of Drug Bacto Unidisk (1969) United States v. Article of Drug Ova II (1975)

→ FDA successfully established that antibiotic sensitivity disks fall under the drug definition → FDA failed to prove that a home pregnancy testing kit is a drug because the court determined that pregnancy is not a disease so the kit is not a diagnostic test for a disease

The Orange Book = Approved Drug Products with Therapeutic Equivalence Evaluations

→ FDA uses a two-letter coding system for the therapeutic equivalence evaluations of multi source drug products → The first letter of the code is either an A or B -Products rated with the first letter A are considered therapeutically equivalent to a reference drug product -Products rated with the first letter B are not considered to be therapeutically equivalent for a variety of reasons, including that they may have documented bioequivalence problems to a reference drug product or there may be a significant potential for such problems and no adequate studies demonstrating bioequivalence → may also indicate that the quality standards are inadequate, or the FDA has insufficient data to determine therapeutic equivalence, or the drug product is still under review → The second letter of the code more specifically describes the dosage form or nature of the product

Medication Guides

→ FDA wanted Medication Guide programs for drugs posing a "serious and significant concern" → FDA determined that if one or more of the following circumstances exists regarding a drug product, there should be a Medication Guide: 1) That patient labeling found help prevent serious adverse effects 2) That the product has serious risks relative to its benefits or which the patent should be aware to decide whether to use or continue to use the product 3) That patient adherence to directions is crucial to the drug's effectiveness → FDA acknowledged that MedGuides would be required for very few products, "no more than 5 to 19 products per year" → Should include approved uses for the product, circumstances when the product should not be used, serious adverse reactions, proper use, cautions, and other general information

Consumer Medication Guide (CMI)

→ FDA wanted a program to provide useful written patient information to accompany every new prescription so the agency proposed distribution goals and performance standards for patient information and left it up to the private sector to accomplish them → if the private sector failed to reach these goals and meet the standards, the agency indicated that it would become necessary to federally establish a comprehensive patient information program → The law requires that 95% of patients receiving new prescriptions must receive useful written information about their medications by 2006 → failure of the price sector to implement a program within 4 years of the law's passage would results in reinstatement of the original FDA-mandated proposal → Was not met since there were flaws in CMI including formatting that is too small and crowded, inconsistent word counts with some CMI being extremely lengthy and repetitive, lack of clear action steps patients should take in the result of an adverse event, lack of clear organization and prioritization of information, and cluttering of important information with unnecessary verbiage

Nutraceutical Corp. v. Crawford (2005) Nutraceutical Corp. v. Von Eschenbach (2006)

→ FDA wanted immediate removal of ephedrine alkaloid dietary supplements (EDS) after some high profile athletes died → however, EDS manufacturer sued the FDA in court contending that the regulation was invalid → court ruled in favor of the plaintiff and invalidated the regulation on the basis that the FDA improperly applied a risk-benefit analysis and failed to provide sufficient evidence that EDS poses a significant risk in the dose recommended → FDA appealed → court sided with the FDA reversing the district court's decision and reinstating the regulation banning EDS products because the EDS manufacturers could not present additional evidence about EDS but rather are limited to review of the FDA's administrative record

Omnibus Budget Reconciliation Act of 1990

→ Focuses on informed decisions by patients rather than on decisions by government or health care providers on behalf of patients → Seems to recognize the medical importance of off-label indications by accepting information in professional compendia (which may list a drug's off-label indications in addition to its labeled indications) as a standard in determining appropriate drug use for Medicaid patients (some contend however that OBRA '90 actually restricts off-label indications because many off-label indications are not stated in compendia sources)

Pearson v. Shalala (1999)

→ Four dietary supplement manufacturers, who had their health claims rejected by the FDA, successfully argued that requiring premarket approval of health claims violates the First Amendment, and that the FDA lacks sufficient criteria for explaining why a health claim does not meet the "significant scientific agreement" standard → Court agreed that complete suppression of health claims, unless they are false or misleading, is too restrictive when disclaimers on the label would accomplish the FDA's objective

United States v. Articles of Drug...Lannett Co. (1978) Premo Pharmaceutical Laboratories, Inc. v. United States (1980)

→ Generic manufacturers grew frustrated that their ANDAs took so long to be approved and were suffering economic losses so argued with the court that because the active ingredients in the parent drugs had already been approved as safe and effective, their generic drugs were not new drugs and therefore the FDA had no statutory authority to withhold the approval of generic drugs → The FDA countered that new drug status is warranted for generic drugs because their safety and efficacy cannot be determined until such questions as the methods of manufacture and proof of bioequivalence are answered → US Supreme Court ruled that a generic drug is a new drug, thus subject to FDA approval

Risk Evaluation and Mitigation Strategy (REMS)

→ Granted to the FDA by the FDAAA, the FDA can require a drug product sponsor to establish special procedures directed at patient safety to manage known or potential serious risks of the product → Includes distribution of Medication Guides, a patient package insert, a communication plan aimed at health care professionals, or Elements To Assure Safe Use (ETASU) → Education programs for prescribers

Investigational New Drug Clinical Testing

→ If the FDA does not reject the IND request within 30 days of submission, human clinical testing may begin Phase 1: involves a small number of subjects -Mainly to examine the drug's toxicity, metabolism, bioavailability, elimination, and other pharmacological actions -Doses of drug are initially low, then gradually increased -Purpose: to detect adverse effects, NOT to determine efficacy -Requires patient consent in writing Phase 2: tested on a limited number of patients who actually have the disease for which the drug is an intended treatment -Continue to conduct pharmacological testing to further determine the drug's safety -Purpose: determine efficacy of the drug and the dosages at which the efficacy occurs -Requires patient consent in writing Phase 3: drug is tested for safety and efficacy in hundreds or even thousands of patients -Often occur in actual clinical settings, such as physicians' offices and hospitals -Usually double-blinded and compared with a control group that receives a placebo -Patient consent may be oral (and recorded in the patient's medical records) or written

Federal Anti-Tampering Act of 1982

→ Made it a federal offense to tamper with consumer products and required tamper-resistant packaging → Tampering is defined as improper interference with the product for the purpose of making objectionable or unauthorized changes → Gave regulatory authority to the Federal Bureau of Investigation, the US Department of Agriculture, and the FDA

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 the FDA regulations -Allowed food labeling to contain a health or disease-prevention claim when there is "significant scientific agreement" approved by the FDA → supplier must submit a petition containing considerable information and evidence supporting the claim -Ex: General Mills Cheerios made a claim that "you can Lower Your Cholesterol 4% in 6 weeks" and "Did you know that in just 6 weeks Cheerios can reduce bad cholesterol by an average of 4%?" → just because the FDA approved a permissible claim does not mean companies can attribute their product to any degree of risk for a disease or condition

United States v. Guardian Chemical Corporation (1969)

→ Manufacturer discovered that is product, which was wold for the purpose of cleansing dairy apparatus, but was also effective in treating kidney and bladder stones → company prepared and distributed brochures to the medical profession to promote its product, Renacidin (intention for advertisement/informing health professionals but did not contain all the required information for labels/labeling) → FDA contended that Renacidin was a drug and that the bottles and brochures were misbranded because they did not contain the label and labeling information required by law → Court agreed with the FDA, holding that printed pamphlets or brochures need not be shipped with the article to constitute labeling and they many be sent either before or after the article and still "accompany" it as long as the distribution of the drug and the brochures are part of an "integrated distribution program" to sell the product

Imitation Drugs and the United States v. Articles of Drug (Midwest Pharmaceuticals)

→ Midwest distributed and promoted a drug containing caffeine, ephedrine, and phenylpropanolamine and its advertisements for the drug contained pictures of capsules and tablets that looked exactly like various well-known amphetamine-type controlled substances → Definition: -Identical in shape, size, and color -Similar or virtually identical in gross appearance -Similar in effect to controlled substances

USP/NF Official Compendium

→ NF = monographs of inactive ingredients and USP = active ingredients → In 1980, combined into one book serving as the standards for drugs in the US

Food, Drug, and Cosmetic Act of 1938

→ No new drug can be marketed until proven safe for use under the conditions described on the label and approved by the FDA → Expanded the definitions of misbranding and adulteration requiring that labels must contain adequate directions for use and warnings about the habit-forming properties of certain drugs → Applies to cosmetics and devices as well → Exempted drugs marketed before 1938 from the requirement that new drugs be proven safe before being marketed -1941: FDA required batch certification of the safety and efficacy of insulin to ensure uniform potency; also amended to include penicillin and other antibiotic drugs → this was eliminated under the Food and Drug Modernization Act of 1997

Pharmanex, Inc. v. Shalala (2001)

→ Pharmanex challenged the FDA's decision that its product, Cholestin, which contained red yeast rice, is regarded as a health food so their product is a dietary supplement → Court agreed with FDA because the FDA established that Cholestin contained significant amounts of lovastatin, a drug approved by the FDA in 1987 and proved that Pharmanex carefully manufactured the product of Cholestin to contain high levels of lovastatin not found in traditional red yeast rice = proved that the company was marketing lovastatin, not traditional red yeast rice → Pharmanex replied that lovastatin was present in some foods marketed in the US long before it was approved by the FDA and therefore, it must be considered a dietary supplement → Court agreed with the FDA's interpretation that traditional red yeast rice does contain lovastatin and that lovastatin itself was not marketed as a dietary supplement, food, or food component, prior to 1987 (is marketed as a drug)

Pure Food and Drug Act of 1906

→ Prohibited the adulteration and misbranding of foods and drugs in interstate commerce however it did not prevent false or misleading efficacy claims and misbranding only referred to the drug's identity (strength, quality, purity) -Novel The Jungle by Upton Sinclair described atrocious adulteration problems in the meat industry - concern for the risks to public health and safety associated with unsanitary and poorly labeled foods and drugs prompted Congress to make this act -Did not require label to list the ingredients, include directions for use, or provide warnings -Failed to regulate cosmetics and devices

Abbreviated New Drug Application (ANDA)

→ Proof of safety and efficacy was not required but rather only proof of bioequivalence and proof of acceptable manufacturing methods and controls → Allowed manufacturers of generic drugs to continue to market their products pending the approval of their ANDAs

Orphan Drug Act of 1983

→ Provides tax and exclusive licensing incentives for manufacturers to develop and market drugs or biological for the treatment of "rare diseases or conditions" (affecting fewer than 200,000 Americans)

USP Compendia

→ Published by the United States Pharmacopeial Convention (USPC) → Independent, private organization founded by physicians and pharmacists who were concerned that various medicinal ingredients and preparations under the same names, differed considerably in potency, quality, and composition → set uniform standards → USP monographs establish approved titles, definitions, descriptions, and standards for identity, quality, strength, purity, packaging, stability, and labeling for a drug

FDA Safety and Innovation Act of 2012 (FDASIA)

→ Reauthorize PDUFA and allows the FDA to continue to collect user fees from manufacturers seeking NDAs or medical device approvals, but also adds new fees for generic drugs and biosimilars → Other 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 → Enables the FDA to inspect foreign drug manufacturers more regularly and requires the agency to target problematic manufacturing sites

Food and Drug Administration Amendments Act of 2007 (FDAAA)

→ Reauthorize and amend many drugs and medical devices that were set to expire → Provided FDA with new funding and more authority over drug safety → FDA has enhanced responsibilities and authority to regulate drug safety: mandate labeling changes related to safety, require clinical trial data reporting and registries, require postmarked clinical studies to assess risks, require companies to implement risk evaluation and mitigation strategies (REMS) when necessary

Drug Efficacy Study Implementation (DESI) 1968

→ Required generic drugs to establish efficacy comparable to pioneer (brand name) drugs → FDA commissioned the National Academy of Sciences National Research Council to study the drugs and submits its recommendations: 1. Effective 2. Probably effective (additional evidence required) 3. Possibly effective (little evidence submitted) 4. Ineffective (no acceptable evidence) 5. Effective, but...(effective but better, safer, or more conveniently administered drugs are available) 6. Ineffective as a fixed combination

Color Additive Amendments of 1960

→ Required manufacturers to establish the safety of color additives in foods, drugs, and cosmetics → FDA can approve a color for one use, but not for others (ex. external use only) → Delaney Clause: prohibits the approval of any food additive that might cause cancer

U.S. v. Rx Depot, Inc. (2003)

→ Rx Depot operated stores throughout the US but solicited patients to mail, fax, or deliver their prescriptions to one of its stores but would then transmit the prescription and a medical history form from the patient to a participating pharmacy in Canada → A Canadian doctor would rewrite the prescription, and the Canadian pharmacy would fill and ship it directly to the patient in the US → Court concluded that it was sympathetic to patients who cannot afford prescription drugs at US prices, but that Rx Depot was violating the law and thus granted the FDA's motion for an injunction, requiring that the defendant cease its operations

Prohibited Acts

→ Section 301 of the FDCA → No adulterated or misbranded products in interstate commerce, no counterfeit drug, issues with the labeling, no unsafe dietary supplements → Violators: imprisoned for not more than 1 year, fined not more than $1000, or both → Second offense: imprisoned for up to 3 years, and/or fined $10,000

Drug Price Competition and Patent Term Restoration Act of 1984 (Waxman-Hatch Amendment)

→ Streamline the generic drug approval process while giving patent extensions, in certain cases, to innovator drugs → Make generic drugs more readily available to the public and provide incentives for manufacturers to develop new drugs