Lecture 4: FDA Regulation of Pharmacy Practice (1.31.25)

“Approved Drug Products with Therapeutic Equivalence Evaluations”

• Also known as FDA’s “Orange Book”

• Equivalence ratings for thousands of products

• Equivalence ratings for thousands of products

• Now strictly a search engine

• First published in 1979 to support state substitution programs

• Read: Preface to 34th Edition in Canvas

• First published in 1979 to support state substitution programs

Officially required by Waxman_hatch in 1984

• Read: Preface to 34th Edition in Canvas

• Note: Statistical Criteria for Bioequivalence

• A guide, not legal requirement for professionals

• Adopted by many, but not all states for generic substitution

OB Rating System

• Therapeutic equivalent:” Same clinical effect and safety

• Criteria:

  • FDA-approved (NDA or ANDA)

  • Pharmaceutical equivalent

  • Bioequivalent

• Pharmaceutical equivalent

Same AI, strength, and dosage form

• Therapeutic equivalent:” Same clinical effect and safety

Note: “Therapeutic equivalent” ≠ “therapeutic substitute” as used in professional parlance

Coding System

• 1st letter “A” or “B”

• Generic drugs approved after 1984 should be all “A”-rated

• Substituting a B-rated product would not violate federal law (state law however…)

• 1st letter “A” or “B”

“B” means equivalence suspect or not proven

Rating Method

Only “A”-rated products tend to be the standard in most state substitution processes

OB and Generic Substitution

• Every state now permits pharmacists to substitute generically in some manner

• State laws differ considerably

• Labeling must accurately differentiate generic product from brand

• State laws differ considerably

• “Positive” and “negative” formularies

• “Mandatory” and “professional judgement” substitution

• “Positive” and “negative” formularies

• Positive: May substitute form this list

• Negative: May not substitute from this list

OB and generic substitution: State laws differ considerably

“Mandatory” and “professional judgement” substitution

Imprint codes on solid oral meds

• Ed law §6811-a: must be “clearly marked” to distinguish among “multi-source” (generic) products

Imprint codes on solid oral meds: Also, 21 CFR 206.10

Absent identifying code: adulterated and misbranded

Necessity of a biosimilars process

• After the approval of the first biologic product in 1982 (human insulin produced by E. coli), many new biologic products have entered the market

• Typically, the products are very expensive and increasingly popular in treatment of many diseases

Necessity of a biosimilars process: Typically, the products are very expensive and increasingly popular in treatment of many diseases, including…

• Cancer

• Diabetes

• Asthma/COPD

• Autoimmune disease, and more

Success of biologcs

• Creation of process for “generic” biologics

• It was necessary to change the law, however, before this could happen, the ANDA process (“505(j)”) applied only to FDA-approved products which are all small chemical compounds

Success of biologics: Creation of process for “generic” biologics

Create competition

Creation of process for “generic” biologics: Create competition

• Decrease in price

• Increase in efficiency and innovation

Practical issue: nature of biologics

• The vast majority of these are large, complex, biomolecules'; fusion proteins and MABs

• Unlike traditional products, though they may have similar biologic effects, difficult to reproduce precisely (pharmaceutical equivalent) in the lab

• So, for these reasons, FDA needed authority from COngress to develop a new process

Practical issue: nature of biologics: Unlike traditional products, though they may have similar biologic effects, difficult to reproduce precisely (pharmaceutical equivalent) in the lab

The brand-name companies not required to share their production process; competitors need to develop their own process

Title VII of the Patient Protection and Affordable Care Act of 2010

• Or “Obama Care” as it has come to be known, contained the “Biologics Price Competition and Innovation Act” or (BPCIA)

• Similar to Waxman-Hatch, Congress is seeking a ‘generic’ approval process to promote competition

Title VII of the Patient Protection and Affordable Care Act of 2010: Goals

• Decrease price

• Increase efficiency and innovation

“Biosimilar” definition

• Highly similar to the reference product (brand name)

• Having no clinically meaningful differences in terms of safety, purity, and potency of effect

• Because these are not “pharmaceutical equivalents” (i.e., exact replicas) interchangeability is a key issue

Process

• The BPCIA added §351(k) creating an abbreviated process for approval of competitor products that are “biosimilar” or “interchangeable” with a ‘reference’ (or brand name) product

• Unlike Waxman Hatch, some clinical trials will be required because these are not exact replicas

Sponsor must submit

• Structure analysis

• Functional analysis

• Animal data": toxicity studies, PK/PD, and immunogenicity

• Human clinical studies: PK/PD, immunogenicity, safety, and efficacy

Sponsor must submit: Human clinical studies: PK/PD, immunogenicity, safety, and efficacy

Not required for all indications, however

FDA Safety and Innovation Act of 2012

Title IV: provided for user fees to facilitate new product approval

“Interchangeable”: effect of

• Q: When FDA finds product interchangeable, what is the legal effect on pharmacy practice?

• A: this relates only to the product; FDA does not decide whether to substitute

“Interchangeable”: effect of: A: this relates only to the product; FDA does not decide whether to substitute

Like generic substitution of small molecules drugs, states make these decisions

Regulation of prescribing and dispensing

• Left to the individual states

• States determine the conditions for prescribing and dispensing without regard to FDA’s designation

Purple is the new orange

• FDA News

• On September 9^th, 2014 FDA released the first edition of the “Purple Book”

On September 9^th, 2014 FDA released the first edition of the “Purple Book”

Lists biological products and interchangeable biosimilars

Biosimilars on market

• Numerous

• Interchangeable products are coming to market very slowly

Biosimilars on market: Interchangeable products are coming to market very slowly

• Insulin glargine (Lantus, Semglee, and more)

• Adalimumab (Humira, Amgevita, and more)

• Ranibizumab (Lucentis, Cimerli)

Durham-Humphrey amendments to the Food, Drug, and Cosmetic Act

• AKA: “Prescription Drug Amendments” (1952)

• Distinguish Rx from OTC

• Rx to OTC switching

• Paper/telephone/e-prescribing

• Refills

Rx v OTC

“Adequate directions for use” by the consumer (OTC) vs. “adequate information for use” Rx

Rx v OTC: “Adequate directions for use” by the consumer (OTC) vs. “adequate information for use” Rx

• Learned intermediary (prescriber)

• Pharmacist with independent judgement and counseling

• Patient Rx label and associated labeling

FDA regulation of pharmacy practice: patient information

“Misbranded” (a federal crime) in the absence of “adequate directions for use” (OTC) or “adequate information for use" (Rx)

FDA regulation of pharmacy practice: patient information: “Misbranded” (a federal crime) in the absence of “adequate directions for use” (OTC) or “adequate information for use" (Rx)

In addition FDA asserts it is misbranding for the pharmacist to dispense without additional things it requires

“Misbranded” (a federal crime) in the absence of “adequate directions for use” (OTC) or “adequate information for use" (Rx)

• Patient package inserts (PPI)

• MedGuides

MedGuides

PHARMA v. FDA, 484 F. Supp. 1179 (1980), decided in favor of FDA as under its regulatory authority

Information sources

• Consumer medication information (CMI)

• Patient package insert

• Medication guide

Consumer medication information (CMI)

• Aka: “useful patient information”

• FDA does not regulate currently

Patient package inserts

• 1970: oral contraceptives

• 1977

• Expansion of the program halted in 1981

1977

• Estrogen

• DES

• Progesterone (now repealed)

PPI’s

Dispensed every time patient receives medication

Medication guides

• Proposed in August 1995: limited to products posing a “serious and significant” public health concern, final regulations in 1998

• A high-profile program that FDA views as priority

• Brand-name and all generics

• Brand-name and all generics

Manufacturer must provide, RPh must dispense

Med guide drugs

• Hundreds of mediations and classes of medication (NSAIDs, antidepressants, fluoroquinolones, proton pump inhibitors, for example)

• Often part of REMS

• Required with every fill and refill

• Required with every fill and refill

Note CPG in 2011 distinguishing hospital from community practices

2007: FDA amendments act FDAAA

Accomplished a number of things

Accomplished a number of things

• Permit restriction on distribution

• Labeling changes: on finished prescriptions

• Expanded authority of FDA in the post-marketing phase of the drug development process

• Expanded authority of FDA in the post-marketing phase of the drug development process

Risk Evaluation and Mitigation Strategy (“REMS”)

REMS

• FDA may require REMS in context of need to improve safety

May include some combination of:

• Patient communication plan

• Professional communication plan

• Elements to assure safe use (“ETASU”)

• Patient communication plan

MedGuide or PPI (unlikely both)

Goal of REMS Program

• Allow medication to stay on market by managing emergent risks

• 1. PPIs and Medguides we alraedy know about

• 2. Professional communication plans; prescribers; pharmacists, others

• 3. Other “Elements to assure safe use” (ETASU)

• 3. Other “Elements to assure safe use” (ETASU)

Designed to promote ('“assure”) the medication is safely used

ETASU

May include a variety of things “without which the drug would be unavailable

May include a variety of things “without which the drug would be unavailable:

• Special training, experience, or certification

• Dispensing only in certain settings

• Dispense with restrictions (e.g., documentation of safe use)

• Patient subject to monitoring

• Patient in registry

FDA’s Requirements

• Training (an “element” to assure safe use, or ETASU) is provided to prescribers

• Patient counseling information is provided to prescribers

• Medguides

• Training (an “element” to assure safe use, or ETASU) is provided to prescribers, including:

• Risk/benefit analysis

• Choosing patients appropriately

• Management and monitoring

• Counseling patient on safe use

• Recognition of opioid misuse, abuse, and addiction

Prescription labeling

July 1, 2009

July 1, 2009

“Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088”

“Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088”

• Sticker

• Pre-printed vial cap

• Separate sheet

• CMI

• MedGuide

“Off-label” Uses

• Prescribing for a condition that is not an approved indication

• The “practice of medication” exception for off-label prescribing, though never formalized by FDA is a widely known standard

• Medicare Part D and payment for off-label uses

• The “practice of medication” exception for off-label prescribing, though never formalized by FDA is a widely known standard

Prescribing and dispensing both legal, but will you be compensated?

Poison Prevention Packaging Act

Consumer Product Safety Commission (“CPSC”)

• A variety of substances including most prescription meds and OTCs

• One-time consumer container

• Waiver

• A variety of substances including most prescription meds and OTCs

Exception for OTCs (“one size”)

Exception for OTCs (“one size”)

“This package for households without young children.” or “Package Not Child-Resistant”

• One-time consumer container

Glass or threaded plastic

• Waiver:

You must document request

• Waiver: you must document request

“Blanket” vs. one-time waiver

Exceptions

• NTG sl

• NaFl < 264 mg/package

• “Dosepacks” (pred and methylpred)

• Betamethasone < 12.6 mg

• EES granules < 8 gm erythromycin

• Aerosols for inhalation

• OC, conj est in dispenser packs

• Medroxyprogesterone

• ISDN chewable and sl

• Cholestyramine and colestipol

• Mebendazole tablets < 600 mg

• K⁺ unit doses < 50 mg Eq

• EES tablets < 16 gm

• Pancrelipase

• Sucrase in glycerol/H₂O

Failure to Comply with CRP

• A '“misbranded” product under federal law

• Do not confuse with “tamper evident” packaging

• Do not confuse with “tamper evident” packaging

• Not designed to prevent access by children, but to demonstrate potential tampering

• May be both adulterated and misbranded

Emergency Contraception Timeline

• 1999 Plan B approved; Rx only

• 2001 Citizen’s petition for OTC status

• 2005 lawsuit to force approval of petition

• 2006 FDA approves access with age (18 years) and point of sale restrictions (pharmacy + ID)

• 2009 Tummino v. Torti and Plan B One-Step (PBOS) approved

• 2011 FDA announces approval of PBOS w/o age or POS restrictions

• Same day DHHS overrules FDA’s decision

Case Law, April 5^th, 2013

• Tummino v. Hamburg

• May 1^st, FDA appeals, requests a ‘stay’ on order

• June 5^th, 2^nd Circuit issues stay for PBOS, but denies stay for 2-pill regimen

• June 10^th, FDA proposes approval for PBOS without POS/age restrictions

• June 12^th, approved by court with recommendation to refuse exclusivity

• July 23^rd, FDA grants exclusivity until April 2016

• Tummino v. Hamburg

• Ordered all levonorgestrel-containing products made available without prescription based on “citizen petition”

• The court made several interesting ‘findings’

• The court made several interesting ‘findings’

• ‘Levonorgestrel is among the safest OTC’s’

• ‘The medication only acts on pre-fertilization events; it does not interfere with pregnancy’

• FDA’s decision making process was inconsistent with best practice’

Emergency contraception

One-dose regimen is available without restriction

One-dose regimen is available without restriction

• No age restriction

• No point-of-sale restriction (not limited to pharmacies)