Federal Regulation of Medication: Dispensing
3 ways a Rx to OTC switch can occur
1. Manufacturer requests (FDA) the switch using SNDA (only that manufacturer's product is switched) 2. Manufacturer petitions FDA - Note- 2001 a payer (Wellpoint, formerly Blue Cross) submitted a Citizen Petition to initiate non-sedating antihistamines switch - Fought by manufacturers, supported by FDA, but FDA did not take action - 2002 Claritin by manufacturer (about to go off patent); 2007 Zyrtec switched 3. OTC drug (monograph) review process - Advisory review panel recommends a switch to the FDA - Binding on all manufacturers of active ingredient
PDMA Reimportation (Prescription Drug Marketing Act 1987)
Allows reimportation of prescription drugs by manufacturers only Importation of prescription drugs by patients technically is not legal FDA allows "personal/compassionate use" exemption: - Patients may import a limited quantity of an unavailable drug for personal use - Does not apply to drugs available in the U.S. - Serious condition; drug unavailable in the U.S. - No unreasonable risk - Name of US physician treating patient, with the drug - Does not apply to drugs obtained via internet
Emergency Contraception 0.75 mg (2 doses) Levonorgestrel - "Plan B"
1999-2006 FDA approved as Rx only Citizen Petition: Switch to OTC (NO age restriction, available to all ages) SNDA (Barr): Switch (no age restr.) SNDA (Barr's #2): Data under 16 YO FDA approved OTC for 18 YO FDA denied 2001 Citizen Petition ~Citizen Petition and SNDAs involved to get to final resolution~ 2009: Tummino case: FDA acted in bad faith on citizen petition; abused its discretion; ordered drug available to 17 YOs; FDA reconsider availability for all ages - July 2009: OTC/BTC for 17 and older; Rx for under age 17 - Feb 2011: SNDA Teva submitted single 1.75 mg dose (Plan B One Step) SNDA requesting OTC for all ages - Dec 7 2011: FDA Commissioner approved SNDA for all ages - Dec 7 2011: HHS Secretary overruled Commissioner: "label comprehension and actual use studies.."data not complete enough; "..cognitive and behavioral differences...between ages." Direction to Comm'r to deny Teva's SNDA - April 5 2013: Fed Ct (EDNY) Ordered Plan B available OTC to all ages - April 30 2013: FDA approved Teva's single dose (1.75 mg) SNDA - May 1, 2013: appeal of April 5 2013 District Court Date - June 5, 2013: 2nd Circ- Make two doses available - June 10, 2013: FDA to court-intent to comply - June 20, 2013: FDA approved Teva's SNDA for single (1.75 mg) dose Plan B One Step for all women of childbearing age - Teva- 3 years exclusivity (FDA wouldn't consider a second app for another manufacturer until after passing of 3 years) **Took from 1999-2013 to do this!***
Compounding Quality Act November 27, 2013
"Pharmacy compounding" Removed unconstitutional advertising provisions CGMP, adequate directions for use, misbranding, and New Drug provisions do NOT apply if: - Compounded for individual patient - Based on valid prescription - Compounded by licensed pharmacist/physician Anticipatory compounding: limited quantities, based on history of pharmacist/physician Compounding with Bulk Drug Substances - Comply with USP/NF, USP Compounding Ch. - If no monograph, use component of approved drug - If neither, must be on drug list issued by Secretary Non- Bulk = Comply with USP/NF, USP Ch. May NOT compound if: - Drugs withdrawn for SAFETY/EFFICACY reasons, and on Secretary's published list - Essentially a COPY of commercially available drug - Drugs with "DEMONSTRABLE DIFFICULTIES to compound." Drugs may be compounded if: - State MOU with FDA re: inordinate I/C; appropriate investigations of complaints about compounded drugs shipped out of state. - No MOU and I/C NMT 5% of total Rx orders - FDA and NABP...
DSCSA Tracing Requirements
- "Trading partners" (ex: manufacturers, wholesalers, repackagers) required to provide subsequent purchasers product tracing information. - Capture tracing info - Maintain records NLT 6 years - FDA exercising enforcement discretion - Guidances at fda.gov - PDMA Regs
Alcohol Regulations
- Bureau of Alcohol, Tobacco, and Firearms (ATF) controls the sale of alcohol - Ethyl alcohol for ingestion is highly taxed - Certain entities may purchase tax-free alcohol (95% ethanol- 190 proof) for scientific, mechanical, or medicinal purposes: Hospital (NOT RETAIL) pharmacies may purchase it: - Cannot be used in food or beverages - Meds made with it may not be sold to outpatients - Storage in secure, locked room and inventory of use must be kept
Medication Guides (MedGuides)
- FDA requires written patient information for drugs where: 1. Pt labeling would help PREVENT SERIOUS ADVERSE EVENTS 2. Product has SERIOUS RISKS of which pt should be aware 3. PATIENT ADHERENCE to directions is crucial to EFFECTIVENESS - Manufacturer writes them; private sector group considers them; FDA approves them before distribution - Required for more than 180 drugs - Ex of drugs for which MedGuide must be provided with dispensed product: Abilify Effexor Gabitril NSAIDs Warfarin
Patient Package Inserts
- FDA rules require the provision of PPIs for certain products - Must be provided to patients receiving the following: Estrogen- containing products Oral contraceptives Oral diethylstillbestrol (DES) - Patients receiving this product must receive PPI: a) with every dispensing in community settings or b) prior to the first dose and every 30 days thereafter as long as the therapy continues in institutional settings
"Useful" Written Patient Information
- Info generated by pharmacies for patients - Supplement to oral counseling - Federal law required 95% of pts receive "useful" info by 2006 - Follow up study conducted by FDA through NABP in 2008: 94% receive written info but only 70% is useful --> formatting too small, crowded (too lengthy, info repeated; lack of clear direction when adverse event occurs); info not prioritized
FDA Inspection of Pharmacies
- Inspectional authority: 704 - Typically, FDA does NOT inspect pharmacies - If manufacturing is occurring, will inspect - No need for a warrant - Refusal of entry, access to, and copying of records is a violation of FDCA - Penalty: up to 1 year; $1,000 fine or both
Durham- Humphrey Amendment Prescription Label Requirements
- Name, address of dispenser - Serial # - Date of filling - Prescriber name - Patient name - Directions for use - Cautionary statement, if any States may have additional label requirements: - Name/strength of drug - Name/initials of RPh - Expiration or beyond use date- USP guideline for "beyond use date" for multiple unit containers (typical prescription vial) is no later than the manufacturer's expiration date or one year from date of dispensing. - Patient's address - Manufacturer/distributor name - Lot number Exempt from 352 Misbranding- but NOT for: - False or misleading statements - Imitation drug - Offered under name of another drug - Deterioration, packaging, and labeling if needed - Poison Prevention Packaging Act
Types of Patient Information
- Patient Package Inserts = FDA required for certain drugs (originally oral contraceptives, estrogens, 1970s) - Medication Guides (MedGuides) = FDA required for certain drugs- 1998 - Useful Written Patient Information (Consumer Medication Information CMI) = 1995 FDA proposed reg/1996 law- private sector distribution goals for new prescriptions; studies in 2001, 2008; Not meeting objectives as to qualify info and adequate distribution.
Compounding v. Marketing
- Pharmacies are EXEMPT from manufacturer's REGISTRATION requirement if they "do NOT manufacture, prepare, propagate, compound or process drugs or devices for sale other then IN THE REGULAR COURSE OF BUSINESS" - If a pharmacy compounds in the regular course of business it is NOT considered a manufacturer. (US v. Baxter) - Manufacturing requires the entity to REGISTER, to LIST the drugs with FDA, and to comply with cGMP regulations - Pharmacies that repackage OTC products or in any way change the container, wrapper, or labeling for resale must register as manufacturers/repackagers. TRADITIONAL compounding is NOT manufacturing Is a compounded drug an unapproved "new drug"? - FDA has said yes - Federal courts have disagreed - Legal challenges resulted in mixed opinions (2002, 2006, 2008, 2011) - Compliance Policy Guides CPG 1992, 2002
Purchase and Resale of Drugs by Hospital, Health Care Entities
- Receipt of drugs by hospital pharmacy, pursuant to licensed practitioner's request - Documentation required: Name, address of requesting prescriber Hospital name, address Name, address, signature of recipient Name, strength of drug Quantity, lot of number Delivery date PDMA- prohibits sale, purchase, trade (or offers to do so) of prescription drugs purchased by a hospital, health care entity, or charitable organization. - Exceptions: Sale to patients pursuant to prescriptions, sales among hospitals or nonprofits under common control or affiliates, emergency shortage situations
Compounding Quality Act Guidances
- Registration for Outsourcing Facilities 503B - Fees for Human Drug Compounding Outsourcing Facilities Under Sections 503B and 744K of the FD&C Act - Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B These 3 more recent
Poison Prevention Packaging Act 1970
- Requires special packaging to protect children under the age of 5 years old from accidental poisoning - Requires child resistant containers for packaging most OTC drugs and nearly all Rx drugs --> child resistant (80% of children under 5 YO can't open the package, 90% of adults can open the package) - Enforced by the Consumer Product Safety Commission (CPSC) All new and refilled oral prescriptions must have a child resistant closure UNLESS: - PRESCRIBER indicates that none can be used (cannot provide a blanket waiver) - PATIENT indicates they do not want such a closure (Patient may provide a blanket waiver- advisable to have the pt provide written directive. ex: on the back of prescription and reconfirm on a regular basis) When preparing refills, both parts of the prescription vial (body and cap) of plastic container must be replaced- if container is glass, only plastic cap must be replaced Manufacturers may market one size of an OTC product in noncompliant package - "This Package for Households Without Young Children" or - "Package Not Child-Resistant" (for smaller labels) - Manufacturers must also supply the product in packages that are child resistant
Third Class of Drugs
- Restricts sale of certain drugs only to pharmacists- Behind the Counter (BTC) - Proposed early in 1970s - Has existed for years with certain C-V meds - Most recent- emergency contraceptives - FDA was seriously considering establishment of this class- public meeting/hearings in 2007, 2012. Supported by pharmacy, insurance groups. Opposed by AMA
PDMA Regulates Drug Samples (Prescription Drug Marketing Act 1987)
- Sale, purchase, trade of samples prohibited: mere presence of any sample in a RETAIL pharmacy- evidence the sample was obtained illegally (draft FDA regulation) - Pharmacy of a HOSPITAL or HEALTH CARE ENTITY may receive samples at the request of a license practitioner, provided there is a receipt containing all required info. - Physicians must make written request to the manufacturer for samples - Manufacturers must: Maintain inventory of all samples Maintain list of all sale representatives Ensure samples are stored appropriately Notify FDA of any loss or theft
Electronic Rxs and EPCS
Pre-Durham Humphrey Act- written Rx only Present day practice: Fax (image) and data (e-mail)
Drug Advertising by Pharmacies
Price advertising considered "reminder advertising" by FDA and allowed under 21 CFR 200.200 if certain conditions are met: - Purpose is to provide PRICE INFO ONLY not info on drug safety, efficacy, indications - Ad must contain brand (if any) and generic names, strength, dosage form, price - Price must include all charges to consumer; mailing fees may be stated separately - Other info allowed, such as professional services State laws fovern other aspects of drug advertising: - Before 1976, many states prohibited drug price advertising as "unprofessional conduct." Virginia State Board of Pharmacy v. Virginia Citizens Consumer Council- declared such laws violated the 1st amendment right to free speech (overturned prohibition of pharmacy advertising)
REMS
Risk Evaluation and Mitigation Strategies "a safety strategy to manage a known or potential serious risk associated with a medicine and to enable patients to have continued access to such medicines by managing their safe use" - REMS unique to each drug; benefit- risk - Ex: Chantix, Androgel - Part of NDA approval or added to already approved drugs with discovered safety questions
Generic substitution- Governed by states, FDA recommendations
The FDA's "Orange Book" - "Approved drug products with therapeutic equivalent evaluations" - "Pharmaceutical equivalent" drugs have the SAME: active ingredient, strength, dosage form - "Therapeutic equivalence" bioequivalent, expect same clinical effect and safety Not all marketed drugs are listed, only those for which FDA has data
Off Label Uses of Drugs
Use of a drug for indications NOT listed in approved labeling Background: 1. Clinical practice is ahead of drug approval process 2. Mfrs may seek NDA approvals for minimal number of indications to expedite approval process; later submit ANDA or SNDA for additional indications added to labeling later. Marketing strategy. - FDA: Off label prescribing and dispensing is LEGAL - Professional judgement required to dispense- duty to ensure risk of harm is avoided. Counseling?
Prescriptive Authority
Who can prescribe? - MD, DO, OD - DDS, DPM, DVM - NP, PA, APN, LCP - RPh Scope of prescriptive authority; area of practice --> determined by STATE practice act and rules Collaborative Practice- Mechanism for other professionals to "prescribe" via agreement with traditional prescriber Refill authorization can be COMMUNICATED by agent
Durham-Humphrey Amendment - 1951
CHANGED PHARMACY PRACTICE - Authorized oral prescriptions - Authorized refills - Created Rx and OTC classes of drugs "(1) A drug intended for use by man which- (A) because of its TOXICITY or other potentiality for harmful effect, or the METHOD OF ITS USE, or its COLLATERAL MEASURES necessary to its use, is not safe for use except under the supervision of a PRACTITIONER licensed by law to administer such drug; or... (B) is LIMITED by an approved APPLICATION (NDA/ANDA) under section 505 of this title to use under the professional supervision of a practitioner licensed by law to administer such drug..upon an oral prescription... reduced promptly to writing or by refilling (written or oral) prescription..." Rx drugs- unsafe for use except under the supervision of a prescriber due to TOXICITY, METHOD OF USE, or COLLATERAL MEASURES. - Toxicity and method of use- may cause harm without supervision - Collateral measures- if pt takes drug for a condition it cannot treat or cure, harm may occur by postponing effective treatment.
Poison Prevention Packaging Act Exemptions
Exemptions include but are not limited to: - Sublingual nitroglycerin tablets - Sublingual and chewable isosorbide dinitrate products in doses of 10 mg or less - Sodium fluoride products containing not more than 264 mg of sodium flouride per package - Anhydrous cholestyramine or colestipol powder packets - Methylprednisolone dose pack - Mebendazole tabs, no more than 600mg/package - Unit dose potassium supplements - Aerosol inhalation therapy products - Oral contraceptives in memory-aid packages - ASA and APAP effervescent tablets or powder - Drugs for institutionalized patients
Compounding Quality Act Enhanced Communications
FDA, with NAPB, to establish a mechanism to receive information from State Boards of Pharmacy re: actions taken against compounding pharmacies or concerns about compliance. Actions include: warning letters, sanctions, penalties for state violations, suspension, revocation, recalls etc (FDA would defer to state licensing authorities. Warning letter- sent to highest ranking person and giving them 15 days response time as to what actions will be taken to correct observations that were made and to prevent recurrence of activities in future)
Compounding Quality Act "Outsourcing Facilities"
Facility, at one geographic location, that: - Compounds STERILE products - Elected VOLUNTARILY to register with FDA - Complies with all sections of 503B - May or may not obtain Rxs for SPECIFIC PATIENTS (unlike 503A) (503A- compounding; 503B- moves operations/outsourcing facilities more to manufacturing; locations that manufacture sterile products; manufacturers have to register, pharmacies don't - voluntary) Facilities may compound using bulk drugs if drugs are: - On a list established by Secretary - On drug shortage list AND - Compliant with USP/NF monograph, if any. - Manufactured in FDA registered facility - Accompanied by C of A Non bulk: comply with USP/NF Facilities may NOT compound - Drugs withdrawn for SAFETY/EFFICACY reasons - Essentially COPIES of approved drugs - drugs with DEMONSTRABLE DIFFICULTIES compounding - Drugs subject to REMS (unless prior approval) - For WHOLESALE Prohibited Act: "If the advertising or promotion of a compound drug is false or misleading in any particular." Facilities must: - Register annually (~65 registered facilities) - Indicate intention to compound shortage list drugs - Report drugs compounded in prior 6 months, incl: Actives, NDC Number, Source of bulk actives, strength, dosage form, package description, number of units produced - Allow FDA risk based inspections - Submit adverse event reports - Pay annual establishment registration fee (not registered until fee is paid, and drugs misbranded) - Pay re-inspection fees
Orange Book 2 Letter Coding
First letter "A" or "B" - "A": therapeutically equivalent to a reference drug (brand name) product - "B": not therapeutically equivalent to a reference drug product - "AB": potential bioequivalent issues resolved (at one time there may have been question of equivalence but it has been resolved so it can be used to substitute) ~Has to be A or at minimum AB to switch~ Orange book is reference, not law but is relied on a lot. - Second letter generally describes dosage form or product nature - If there is more than one "reference drug," then a number is added to the 2 letter code. Ex: extended release nifedipine example Orange Book Facts: Generic drugs approved with ANDA after 1984 should always have "A" rating bc the Patent Term Restoration Act required proof of bioequivalence for approval. Legal authority: - FDCA- does not mandate use of Orange Book; failure to utilize does not violate federal law - HOWEVER many states require Orange Book "A" rating for generic substitution; therefore "A"- "B" or "B"-"B" switches require prescriber approval in most states. - Careful exercise of professional judgement, counseling?
Switching from OTC to Rx FDA's- Burden of Proof US v. Article of Drug- Decholin
Held FDA must prove TWO issues to change an OTC drug to Rx: - TOXICITY and method of use require prescriber supervision, to prevent harm to patient - HARM in postponing effectiveness treatment if use of the drug is inappropriate: consider seriousness of harm, length of delay, quality of advice on label, possibility that drug may relieve symptoms but not cure condition.
