Pharmacy Practice Law Chapter 2

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

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

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

Off-Label Uses Conditions for Disseminating

1) Filed an application for approval for the use 2) Submit to the agency 60 days before dissemination a copy of the information to be disseminated and any clinical trial information the company has 3) Include with disseminated information a disclosure that the use has not been approved, a copy of the official labeling for the product, any other products or treatments that have been approved for the use, the funding source for any studies relating to the use, and a bibliography of scientific publications regarding the use → Due to issues with the First Amendment, guidance documents were published to allow companies to distribute unabridged peer-reviewed articles: -Articles should be accompanied by the approved labeling -Accompanied by a comprehensive bibliography of publications regarding the use (if available) -Disseminated with a representative publication (in in existence) that reaches contrary or different conclusions -Distributed separately from promotional information -Accompanied by a disclosure that the use has not been approved by the FDA -Accompanied by a disclosure of any relationship between the company and the author of the article -Accompanied by a disclosure of any known significant risks or safety concerns not discussed in the article -Does not require that the company have filed an NDA for the use or submitted a copy of the article and related clinical information to the FDA 60 days prior to dissemination

Direct To Consumer Advertising Categories

1) Product claim ads: name the drug and the condition it treats and are subject to the regulations 2) Reminder ads: give the drug's name, but not its uses, and are not subject to the regulation 3) Help-seeking ads: education in nature and do not mention the name of the product, only the name of the company (inform consumer about diseases, mentioning that a physician can treat a particular condition with medications, and urge the consumer to see a physician) → need not conform to FDA labeling and advertising requirements

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

DTC and Ciba-Geigy

Ciba-Geigy was forced to discontinue its DTC advertising of Actigall, a drug used in an effort to dissolve certain kinds of gallstones, in response to FDA concerns → FDA believed that the advertisements misled consumers by intimidating that surgery was the only other choice of treatment → also agreed to cease using celebrities to promote its products

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

Over-the-Counter (OTC) Drug Review

Final monograph on a reviewed ingredient specifies 3 categories the ingredient is placed 1. Category I includes ingredients generally recognized as safe, effective, and not misbranded 2. Category II includes those ingredients that are not generally recognized as safe and effective or that are misbranded 3. Category III includes ingredients for which data available are insufficient to permit classification

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

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

Cruzan v. Director, Missouri Department of Health (1990)

Held that an individual has a due process right to refuse life-sustaining medical treatment

Exclusion Payments or Pay-For-Delay Agreements

Innovator company pays the generic manufacturer not to market its generic (will pay them their 180 day exclusivity)

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

Central Hudson Gas v. Public Service Commission (1980) and the First Amendment

When evaluating the governmental regulation of commercial speech, the factors considered: 1) The speech must not be misleading or related to an unlawful activity 2) The government interest in the regulation must be substantial 3) The regulation must directly advance the government interest asserted 4) The restriction of speech cannot be more extensive than necessary to serve that interest → Issue: which activities, in what manner, and to what extent should the FDA be able to regulate

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

Cutler v. Kennedy (1979)

→ A group of consumers contested the FDA's policy and demanded that the FDA remove all category III products from the market → The court agreed with the plaintiffs that an FDA regulation allowing these OTC drugs to be marketed pending the agency's determination of safety and efficacy was an affront to the FDCA's premarketing procedures BUT did not see the need to tell the FDA to remove category III drugs from the market

Sentinel Initiative

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

Abigail Alliance for Better Access to Developmental Drugs and Washington Legal Foundation v. Eschenbach (2006)

→ A public interest group formed on behalf of terminally ill patients sued to enjoin the FDA from enforcing the policy that restricted medical treatment with an IND to those drugs in phase 3 of the NDA process saying that it should allow terminally ill, mentally competent adults to obtain IND drugs that have reached phase 2 → Court disagreed with them and sided with FDA → On appeals, this decision was revered and remanded the district court's decision, finding for the plaintiffs concluding that terminally ill, mentally competent adults have a protected liberty interest under the Due Process Clause of the Constitution to IND drugs in phase 2 when there are not alternative approved treatment options available

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

Federal Trade Commission Act

→ Allows the FTC to prohibit unfair methods of competition and unfair or deceptive acts or practices and to regulate advertising for foods, OTC drugs, and medical devices → CANNOT require companies to submit advertising to it for premarket approval but rathe must act AFTER the fact → Devotes top priority to advertisements in which the accuracy of the claims is difficult for consumers to verify such as OTC drug advertisements and deceptive advertising claims of OTC products → Requires verification from company depending on type of advertising claim made, the type of product, the consequences of the false claim, the degree of reliance by consumers, and similar factors → FTC has the authority to issue cease-and-desist orders, issue corrective advertising, and require advertisers to make affirmative disclosures when necessary to qualify certain statements (half truths) or to disclose certain adverse consequences of a drug → FTC regulates food advertising while FDA regulates food labeling

"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

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

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 of 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

Medical Devices Classification

→ Class I: use "general controls" that require device manufacturers to register the facility and list their products with the FDA, provide premarket notification in some cases, maintain records and reports, and adhere to good manufacturing practices -Examples: needles, scissors, examination gloves, stethoscopes, toothbrushes → Class II: general controls are insufficient so products must meet specific performance standards established by the FDA before the FDA will permit marketing -Examples: insulin syringes, infusion pumps, thermometers, diagnostic reagents, tampons, and electric heating pads → Class III: must have premarket approval because they are life-supporing or life-sustaining or they present a potential unreasonable risk of illness or injury -Examples: pacemakers, soft contact lenses, and replacement heart valves

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

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

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

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

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

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

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

Washington Legal Foundation v. Friedman (1998) Washington Legal Foundation v. Henny (2000)

→ FDA's regulation on industry-supported educational programs and its guidance for manufacturers was challenged by a public interest group alleging that it violated the First Amendment → Court agreed that the guidance was overly restrictive and enjoined the FDA from prohibiting companies from being involved in the symposia content and discussing off-label uses as long as there is disclosure that the use is unapproved → FDA appealed this decision arguing that a violation of the guidance is not illegal per se rather the guidance only serves as a "safe harbor" informing manufacturers of conduct that would not be challenged by the agency → Court found that no constitutional issue existed, vacating the district court's decision that the guidance was unconstitutional → Some of the restrictions for promoting off-label uses were ruled unconstitutional on First Amendment grounds, but the court of appeals allowed the provisions (See below) to remain after the FDA changed its position to assert that the FDAMA provisions were not requirements, but merely established "safe harbor"

Porter & Dietsch, Inc. v. Federal Trade Commission (1979)

→ FTC challenged the advertising claims that the manufacturer made for X-11 diet tablets contending that the advertisements were valise and misleading because they proclaimed that users of the tablets can lose weight without changing their eating habits, that users will lose a significant amount of weight, and that X-11 contains a unique ingredient → The advertisements also contained material omissions, including the information that persons with certain diseases should use X-11 tablets only as directed by a physician → Court decided in favor the of the FTC because the company could produce no scientific basis for its claim of weight loss and that the "unique" ingredient of phenylpropranolamine had been in use for years and was hardly unique → FTC admitted evidence showing that phenylpropanolamine could produce adverse effects in individuals with certain medical conditions, and the court agreed that this omission in the advertisements made them false and misleading → FTC was also brought action against Pay'n Save drugstore chain as it received advertising materials for the X-11 tablets for publication under its name → Had no knowledge that the advertisements were false or unsubstantiated but the court found the drugstore chain liable and cited section 12(a) of the act: "It shall be unlawful for any person, partnership, or corporation to disseminate, or cause to be disseminated, any false advertisement" = NO EXEMPTIONS

Warner-Lambert Co. v. Federal Trade Commission (1977)

→ FTC ordered Warner-Lambert to cease and desist misrepresenting the efficacy of Listerine mouthwash against the common cold → Company appealed the FTC's findings in court, arguing that the FTC did not have the evidence to sustain a finding of false and misleading advertising → Court found for the FTC after the agency introduced several facts into evidence: -Ingredients of Listerine are not present in sufficient quantities to have any therapeutic effect -Impossible for Listerine to reach critical areas of the body in significant concentration through the process of gargling -Even if the active ingredients could reach critical sites, they could not penetrate the tissues cells, and thus, not affect the viruses -Waner-Lambert's clinical studies were unreliable -Even if Listerine kills millions of germs, it would be of no medical significance because these germs play no role in colds → Required Listerine to state "Listerine will not help prevent colds or sore throats or lessen their severity" for a 10 year period amount to about $10 million, but no greater than this time period due to restrictions of the First Amendment

Affordable Care Act: Biologics Price Competition and Innovation Act (BPCIA)

→ Facilitates the approval of generic biologics (biosimilars or follow-on biologics) → Grants the FDA the authority to determine whether a biosimilar is therapeutically equivalent to a reference biologic and thus can be substituted in the same manner as generic drug products → Grants a 12-year marketing exclusivity period to the reference product

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)

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

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

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

Authorized Generic

→ Innovator manufacturer providing a generic version of its brand-name product

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)?

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 not contain lovastatin and that lovastatin itself was not marketed as a dietary supplement, food, or food component, prior to 1987

Biologics/Biologicals

→ Products derived from living organisms, and include viruses, therapeutic serums, toxins, antitoxins, vaccines, blood and blood components, and derivatives applicable to the prevention, treatment, or cure of a disease or condition of humans → Regulated by both Public Health Service Act (PHSA) and the FDCA and licensed by PHSA while being approved by the FDA upon demonstration that the product is safe, pure, and potent, and that the facility meets required standards

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

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

Lanham Trademark Act

→ Prohibits the use of "any false description or representation, including words or symbols" in connection with the sale of any goods or services → Allows private parties a cause of action against false and misleading advertising = allows for a private cause of action and the recovery of monetary damages, as well as injunctive relief → American Home Products Corporation v. Johnson & Johnson (1987): Advil sued Tylenol for false advertising claims by publishing false printed materials and broadcast false television commercials that unfavorably compared ibuprofen with acetaminophen → Tylenol countersued Advil for false comparative advertising of its other OTC analgesic products Anacin and Anacin-3 → court concluded that each part was guilty of misleading advertising and was too complex to determine damages to each party

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 biologicals 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

Fast Track Approval

→ Regulations to expedite the development, evaluation, and marketing of new drugs intended to treat serious or life-threatening illnesses → FDA will expedite the review of the drug if: 1) it is intended for the treatment of a serious or life-threatneing condition and demonstrates the potential to address unmet medical needs for the condition 2) the product has an effect on a clinical endpoint or on a surrogate endpoint reasonably likely to predict clinical benefit → approval will be conditioned on the completion of postmarketing, or phase 4, clinical studies to verify and describe the drug's clinical benefit

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 color additive that might cause cancer

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 (PTRA) of 1984 (Hatch-Waxman Amendment)

→ Statutorily created the ANDA so that the sponsor needs only to submit sufficient information to demonstrate that the generic contains the same active ingredient, route of administration, dosage form, and strength as the pioneer drug; is bioequivalent to the pioneer drug; and has acceptable manufacturing methods and control procedures → Bioequivalence must usually be established through evidence obtained from human clinical trials establishing either that the generic drug's extent of absorption (Cmax) and rate of absorption (AUC) at the site of action are not significantly different from those of the pioneer drug or that the extent of absorption is the same and the rate of absorption is intentionally different, as long as the different is not essential to attaining effective drug concentrations in the body and is considered medically insignificant for the drug → The different rate of absorption must be reflected in the drug's labeling → A company is not required to conduct clinical trials to establish bioequivalence if the FDA can conclude bioequivalence from other studies or other facts submitted by the company → Patent extensions for innovator drug manufacturers: 1. the law allows the FDA to grant innovator drugs patent-term extensions only if the patent has not expired 2. market exclusivity for an innovator manufacturer that develops a new chemical entity or a new use for a previously approved drug (NDA = 5 years from generic drug, previously approved drug = 3 years exclusivity against an ANDA) 4 Types of Certification a Generic Applicant can make: (1) That the NDA holder did not file information on the patent to the FDA (2) That the patent already had expired (3) The date that the patent will expire (4) That the patent is invalid or will not be infringed by the manufacture, use, or sale of the generic applicant's drug

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

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

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

Bristol-Myers Squibb Co. v. Shalala (1996)

→ The federal court held that the FDA could still approve the ANDA for a new generic drug, despite the fact that the manufacturer held exclusivity rights for 3 years to an indication approved by supplemental application and that this indication is not included on the generic's labeling → Bristol-Myers argued that the statute requires that the generic label be "the same" as that of the innovator and because it cannot be the same, the ANDA must be rejected → Court agreed with the government's analysis that the manufacturer's interpretation is at variance with other provisions in the law and legislative intent, that being the new generic drug be safe and effective for each indication appearing on the label is irrelevant → If this prevailed, then every time a manufacturer added a supplemental indication, a new generic drug would be precluded from the market for 3 years

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

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