Lecture 3&4

If supplements can make claims about structure and function, what differentiates them from drugs?

They are not allowed to make therapeutic claims. eg a seller could promote that its cranberry tablets increase the acidity of the urine and help to maintain a healthy urinary tract. If, however, the seller made the claim that its product prevents UTIs, this assertion could make the product a drug under part B of the drug definition.

FD&C prohibits 2 things

Adulteration Misbranding

When can the FDA remove a dietary supplement from market?

on the basis of public safety only if the agency can prove the product is adulterated.

Prescription drug definition under Durham-Hump Ammendment

(1) unsafe for use except under the supervision of a licensed practitioner because of toxicity, method of use, or "collateral measures necessary to its use; or (2) subject to the NDA approval process (all new drugs (requiring NDA) are, by default, prescription status

Post-marketing surveillance of drugs

- Manuf must maintain PMS reports and submit to the FDA reports of serious AEs and new info regarding safety and efficacy. - Necessary cos an investigational drug is tested in a relatively small number of patients compared with the number of patients who may use the drug after it is marketed and long-term adverse effects may not be discoverable before approval.

Corporate officer liability and FD&C Act

- Corporate officers are liable for the acts of their subordinates that violate the Fd&C Act.

New Drug Approval Process

- Drugs must be safe and effective for use under conditions prescribed, recommended, or suggested in the proposed labeling - Triggering events for an NDA: new chemical entity: new substance in existing formulation, even an inactive ingredient; new combination of approved drugs; proportion of ingredients is changed; new intended use; dosage, method, or duration of administration changed. - new drug must be approved by FDA - if the drug is not a generic of a currently marketed drug, this means that the drug manufacturer must apply and receive an NDA

FDA enforcement authority

- FDA mostly issues warning letters to help get the manufacturer on track. - FDA also has the power to institute criminal proceedings (fines, imprisonment), to seize items, order recalls of articles by the manufacturer. - the Act imposes a duty not only to seek out and correct violations, but also to implement procedures to ensure that violations will not occur

New Drug Application (NDA)

- If the phase 3 study results are favorable, the drug's sponsor may submit an NDA to the FDA w/ evidence that the drug is Safe and Effective - Huge submission. Includes data about manufacturing, labeling, and packaging. - If FDA disapproves an NDA, application can have a hearing, but most have failed in court

FDA labeling requirements

- No false or misleading info in any particular - list inactive ingredients - Adequate directions for use on OTC meds for layperson - Adequate information use on Rx meds (aimed at the prescriber: indications, AEs, dosages, routes, freq, C/I, warnings/prec)

: Is a physician legally authorized to prescribe outside of his/her "specialty"?

- State laws grant physicians broad treatment authority and thus the authority to prescribe almost any drug. This applies even to specialists such as psychiatrists and radiologists who, because they are physicians, can legally treat conditions outside their specialty. prescribers such as dentists, veterinarians, and podiatrists have much narrower treatment and prescriptive authority.

black box warning regulations

- To emphasize particularly serious risks in a drug the FDA and most professional organizations agree that they are usually ineffective. Reports indicate that many prescribers are either unaware of the warnings or simply do not heed them

Individual access to investigational drugs

- Treatment IND can be acquired for a specific patient - Physician calls FDA to certify that they tried all options - Have to apply for approval - Can be approved in 24 hours - Must be a drug that is undergoing clinical trials

Med guides present what kind of information? for what groups of drugs?

- are paper handouts that come w/many prescription medications that address issues related to the drug class or particular drug. - FDA's purpose is to retain authority to mandate the medication guide program for drugs posing a "serious and significant concern" - part of REMS

What is the purpose of the adulteration provision?

- designed to regulate the facility and means of production and not the product itself. Reasons: First, it is much easier for the FDA to inspect a relatively few manufacturing plants than the thousands of drug products that these plants produce. Second, the health and safety risk to the public is much lower if the FDA can prevent adulteration rather than wait and remove an adulterated product from the market.

When is a drug considered to be adulterated (even if it's pure)?

- prepared, packed, or held in conditions where it may have been contaminated - Exposed to a container that may have contaminated it - manuf under conditions that do not conform to current GMP • A drug is adulterated if its strength, quality, or purity differs from compendia standards, unless stated on the label; or, if its strength, quality, or purity differs from what is stated on the label.

Per The Durham-Humphrey Amendment, who has the prescriptive authority?

- prescription drugs may be prescribed by a practitioner "licensed by law to administer such drug."

certain structure/function claims made my manuf of dietary supplements

- product will benefit a classical nutrient deficiency disease so long as prevalence is disclosed - Role of dietary supplement in affecting structure or function of the body - characterizing mechanism by which a nutrient acts to maintain structure or function - describing general well-being from consumption of nutrient (e.g., "energizer," "relaxant," "muscle enhancer")

An FDA rule, effective January 1, 2008, requires all dispensed medications (whether original or refill) be accompanied with the MedWatch number and advising that patients should consult with their physician if they believe that they have suffered an adverse drug reaction or call the MedWatch program to report. What are the benefits and drawbacks of this approach?

-good to report but what if the patient wrongly interprets and reports a reaction - Pts might report ADEs that are not associated - Spontaneous reporting systems can lead to reporting bias (where certain reactions are more likely to be reported based on factors like promotional claims, reports in medical literature, media, and publicity of other reactions to the drug)

FDA anti-tampering act

-passed as a result of the tylenol-cyanide scare in 1982 - Requires certain OTC products to have tamper-resistant packaging. without the anti-tampering, the drug is deemed adulterated

DSHEA definition of supplement

A product that is intended for ingestion, is intended to supplement the diet, and contains any one or more of the following: a vit, mineral, herb/botanical, amino acid, dietary substance to increase dietary intake, a concentrate/extract or combo

MedWatch Program

A voluntary reporting system through which health care professionals may submit ADE reports to FDA. Not required by law.

Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach issue

Abigail Alliance was an advocacy group trying to get more access to drugs (Abigail had kidney cancer and was unable to get access to a drug for it) -they are arguing that this infringes on constitutional rights → the only way to change this is by amending the Constitution which is very hard to do -we know they're not arguing that there's an implied exception because the Supreme Court already ruled against that in the Rutherford case

Nutraceutical v Eschenbach (outcome)

After 7 years of investigating EDS, FDA had was sufficient data to declare that EDS poses unreasonable risk and is an adulterated product. FDA did not demand data from Nutraceutical. - original ruling reversed and remanded as FDA appealed the district court original decision and got it reversed, saying that asking the company for evidence does not mean it's putting the burden on them instead of taking it upon themselves; EDS was banned again.

How are biologics regulated?

Although biological products require premarket approval by the FDA and are subject to the FDCA requirements like new drug products, unlike drugs, biologicals are licensed under the PHSA (public health service act)

Misbranding definition? examples?

Any problem with the label/labeling. Dispensing drug without medguide, PPI(for estrogen containing drug), drug that doesn't comply with poison prevention act, no expiration date

How are OTC drugs reviewed for safety and efficacy? why?

By therapeutic class: - First, there were between 100,000 and 500,000 OTC drug products on the market, many of which did not have approved NDAs; reviewing each of these products would overwhelm the FDA's resources. - Second, litigation to remove unsafe or ineffective individual OTC products would be prohibitively time-consuming and expensive. - Third, nearly all the OTC drugs were prepared from only 200 or so active ingredients

DSHEA (Dietary Supplement Health and Education Act) 1994

Commands the FDA to treat dietary supplements as foods rather than drugs. - Thus the FDA cannot require pre-market approval of dietary supplements as it does for drugs. - Manuf doesn't have to provide the FDA with the evidence upon which it relies to support product safety and efficacy. -

Nutrilab v Schweiker (outcome)

Court sides with the FDA. Part C broadens the term drug to include articles intended to affect the structure or function of the body. If part C did not exist the starch blocker would not likely be drugs bc they were not promoted for the prevention or treatment of a disease. Foods were excluded under part C bc all foods affect the function of the body. Court disagreed with Nutrilab saying it didn't fit the statutory definition nor common sense definition of food (for aroma, taste, or nutritional value) - FDCA has also created 2 categories of foods: special dietary foods and medical foods.

Can the FDA regulate dietary supplements as food additives?

DSHEA generally prohibits the FDA from regulating dietary supplements as food additives. Because food additives require premarket approval by the FDA, Congress wanted to ensure that the FDA did not attempt a backdoor approach at requiring premarket approval. Being stripped of premarket approval authority means that the agency must prove that a dietary supplement is unsafe before it can remove the product from the market.

distinguish devices from drugs?

Device does not achieve any of its principal intended purposes through chemical action and is not dependent on being metabolized for the achievement of any of its intended purposes. The term "device" does include in vitro diagnostic products used to aid in the diagnosis of disease or verification of pregnancy.

Nutraceutical Inc. v. Eschenbach

FDA banned ephedra (EDS) after receiving a lot of ADE reports. Collected scientific data, expert reviews, comments etc and concluded that ephedra's beneficial effects (weight loss, increased energy, enhanced athletic performance) are minimal but risk is high: increased risk of heart attack, stroke and death. → FDA can take a supplement off the market but bears the burden of proving it's unreasonably unsafe - After it was banned, EDS manufacturer sued FDA in (Nutraceutical v Crawford) saying this regulation was invalid. They said the FDA didn't meet its burden to prove it's unsafe and put that burden on Nutraceutical - FDA asked for evidence (didn't demand it) -Court ruled in favor of company saying FDA improperly applied a risk-benefit analysis and failed to give enough evidence to show that EDS poses a significant risk at the dose recommended.

FDAAA - Food and Drug Administration Amendments Act of 2007

FDAAA authorizes the FDA to conduct "pre-review" of direct-to-consumer advertisements. First Amendment issues limit FDA to providing "recommendations" about the ads, but FDA may require changes if deemed necessary to address serious risks associated with the drug's use. - Otherwise this would be censorship

professional" advertising vs "consumer" advertising.

FDCA draws no distinction between the two. The same FDA regulations that apply to manufacturer-to-professional advertising apply to manufacturer-to-consumer advertising, except that the FDA has specified that the "adequate provision" for obtaining full labeling information should include four sources: toll-free number; Web page; referral to print advertisement or brochures; referral to health-care provider.

Which Act created generic drug approval process via ANDA.

Hatch-Waxman amendment -> same as The PTRA (patent restoration Act). - Trade-off for innovator manufacturers was extension of patent term from 2 to 5 years. - guarantees manufacturer gets exclusivity even if patent has run out

In order to receive FDA approval, generic drugs must: •

Have same pharmaceutical equivalence: i.e. contain the same active ingredient • be the same strength • be the same dosage form (tablet, capsule, etc.), and • have the same route of administration (oral, topical, injectable, etc.) as the brand name drug. "bioequivalent" to the brand name drug (AUC, Cmax, Tmax) meaning the generic drug will work in the body in the same way (same amount goes into the body within the same time frame) and be as safe and effective as the brand name drug. tolerance +/- 20% Therapeutic equivalence = pharma equivalent + bioequivalence comply w/ cGMP

Are dietary supplement manufacturers required to report ADEs?

In 2006, Congress required manufacturers, packers, and distributors of dietary supplements to report "serious adverse events" to FDA with 15 business days

If a pharmacist does not issue a patient package insert or a med guide that is required, are they violating FDA rules?

It is a misbranding violation of the FDCA

Advertising "off label" uses of drugs

It is legal to prescribe medications for off-label uses, but it is not legal for a manufacturer to advertise off-label uses for its product -> Could be potential misbranding;

In NC, can NPs/PAs dispense under the supervision of a dispensing physician?

Nope. They may only dispense in a place holding a pharmacy permit and the PAs/NPs are subject to oversight by a consulting pharmacist

Nutrilab v. Schweiker background

Nutrilab manufactures a "starch blocker" that blocks the body's digestion of starch for weight loss (alpha amylase enzyme). The year prior, FDA had already classified starch blockers as drugs, requesting they be removed from the market, and Nutrilab filed a complaint that they're actually food. They are made from a protein extracted from raw kidney beans, and the protein acts as an inhibitor of a starch digesting enzyme. FDA has received 75 reports of adverse effects -district court said they were drugs, ordered permanent cease of manufacturing and destroying of existing inventories.

Direct to consumer advertising disadv

Opponents of DTC advertising contend that the practice will raise the cost of health care, create an inappropriate demand for medications and a demand for inappropriate medications, confuse patients, and jeopardize the physician-patient relationship.

two types of labeling mandated by federal law that manufacturers must supply for the patient

Patient package inserts Medication guides For a limited number of drugs, the FDA requires the pharmacist to provide a PPI with the prescription eg OCPs

IND phase studies

Phase I - safety and detect AEs. small # of subjects phase II - Efficacy and dosage in pts w/ the disease. more safety testing Phase III - large RCTs; use of drug in clinical setting. Safety and efficacy at determined doses. 100's-1000's of pts

Durham-Humphrey Amendment

Piece of legislature that created the OTC and prescription drug categories key provisions of the bill: - The amendment also legalized verbal transmission of prescription - legal right for pharmacists to honor refill authorizations indicated by physicians in initial prescription - RECOGNIZED pharmacist in distribution of drug - FAILED to acknowledge pharmacists play a role in drug therapy

Biologics Definition

Products derived from living organisms and include viruses, therapeutic serums, toxins, vaccines, blood etc applicable to the prevention, tx, or cure of a disease or conditions of humans

Risk Evaluation and Mitigation Strategies (REMS)

Program of the FDA, designed to monitor drugs that have a high risk compared to benefit ratio. eg accutane (iPLEDGE). FDA may require specific info from the manuf

Direct to consumer advertising adv

Proponents contend that DTC advertising benefits consumers by providing education, promoting awareness of potential health problems, improving compliance with drug therapies, and lowering drug prices. Pharmacists may benefit, according to the proponents, through increased prescription business and greater public recognition that they are the most knowledgeable and accessible source of additional prescription drug information

FDAAA effect on Med Guides

Since the FDAAA was enacted in 2007, the compliance guide (in 2011), the FDA has the discretion to determine that a new MedGuide should be required as labeling only, and not part of a REMS.

Do medical devices require pre-market approval?

Some medical devices require pre-marketing proof of safety and efficacy. Others do not - Approval process established by Medical Device Amendments of 1976 - Devices marketed prior to 1976 may stay on the market. Manufacturers who can show that a device they want to market is "substantially equivalent" to a "pre-amendment" device may obtain marketing approval through a "510(k)" submission, which is substantially less onerous than pre-marketing approval

Who governs prescriptive authority? Federal or state law?

State law governs whether and to what degree a given health-care practitioner has prescriptive authority. Federal law doesn't say who can prescribe or dispense, state does; this does vary a bit from state to state (every state allows physicians, NPs, PAs, some states let naturopaths prescribe)

United States vs Rutherford

Terminally ill patients unsuccessfully sued the FDA in an attempt to obtain an unapproved drug for cancer treatment (Laetrile) -each and every drug needs to be proved to be safe and efficacious before pts can receive it. Statutory Claim: Safety and efficacy has no relevance to the terminally ill so there are no standards on which to judge the safety and efficacy (basically saying there is an IMPLIED exception in the statute). district courts sided with patients, permitting drug use -- court of appeals found that safety/efficacy was not relevant in terminally ill patients Supreme court reversed district court/appeals court decisions: -- requirements of FDCA must be applied equally to ALL drugs regardless of intended use (congress decided and passed this law in plain language, statute is clear) -- agreement of what will be defined as "terminally ill" is difficult -- safety/efficacy is important

Perez v Wyeth Laboratories (outcome)

The court ruled against wyeth stating that DTC marketing seeks to influence a pts choice, and the company should be responsible for supplying the pt with proper warnings and side effects. Had Wyeth simply supplied the physician with the information about norplant and not DTC, then wyeth had no independent duty to warn patients, as opposed to physicians.

State "Right to Try Laws"

The state law creates an avenue to greatly facilitate off-study administration when patient, physician and the manufacturer are all in agreement regarding the off study use of an eligible investigational agent. The law does not, however, empower a patient to impose a demand on either a provider or a drug manufacturer, nor does it require any entity to provide financial coverage for the drug - If federal law says you can't get access to it, state law can't say you can - this is more of a "feel good" legislation because it doesn't actually do much for the pt as federal law supersedes state law. - These laws allow for pts to go directly to the drug manufacturer but they are not obligated to provide the drug

Can a manufacturer/supplier of a supplement include an article that has been approved as a new drug in its products?

They can't and also cannot make therapeutic claim about the article and call it a supplement.

Class III Medical Device definition

This class of medical device applies to life-supporting or life-sustaining, or serious risk of harm; or serious risk of harm; must obtain pre-market approval. - By default, all new devices are placed in Class III unless FDA is satisfied that the device is substantially equivalent to a pre-1976 device. eg heart valves, hip implant

Class I Medical Device definition

This class of medical device is very simple by design and has a very low potential to cause harm. eg compression socks, Iv stands, bandaids

Do dispensing pharmacists have to comply with all the FDCA labelling requirements?

Without the Durham-Humphrey Amendment, pharmacists would be required to label every dispensed prescription drug pursuant to the same requirements that manufacturers must meet.

Perez v Wyeth Laboratories (issue)

Wyeth began a massive ad campaign for Norplant as a reversible contraceptive that was directed at women and failed to warn of any dangers or side effects. Wyeth argued that the "learned intermediary" doctrine applies which assumes that manuf are responsible for providing info to physicians and physicians should relay that information to the patient.

Are dietary supplement manufacturers required to comply with CGMP?

Yes, FDA passed a rule in 2007 requiring cGMP to ensure products are not adulterated or misbranded. - The regulations also require manufacturers to evaluate the identity, purity, quality, strength, and composition of their products.

Under NC law, can a pharmacist refuse to fill a prescription?

Yes, if in their professional judgment, it would be harmful to the recipient, it is not in the recipient's best interest of if there is a question as its validity. - Practically, however, it is difficult for a pharmacist to know why a prescriber has prescribed a given drug.

Investigational new drug (IND) application

a document to the FDA to allow clinical testing of a new drug or product in humans, otherwise cannot ship across state lines. - Informed consent is required for participation in any IND clinical studies. - FDA can terminate IND any time and it's non-negotiable.

Package inserts regulations

a pamphlet that must accompany the drug product and contains the essential scientific and medical information needed for safe and effective use of the drug by healthcare professionals. 1) FDA regulates content and format (FDA approves of package insert) 2) must contain a summary of scientific info that is needed for SAFE and EFFECTIVE use 3) info must be informative, accurate and not promotional in tone and canNOT be FALSE or MISLEADING 4)MUST have SPECIFIC info under the listed headings in a SPECIFIC order New format approved in 2006

Does FDA go after dietary supplements that are in violation of CGMP?

because dietary supplements do not require FDA approval, the FDA will generally not identify products in violation of CGMP before they reach consumers.

Are biosimilars interchangeable?

biosimilar cannot be substituted with the original product when prescribed. In order to demonstrate interchangeability, the applicant must establish that the biosimilar can be expected to produce the same clinical results as the reference product without any greater risk. The law grants a 12-year marketing exclusivity period to the reference product.

Class II Medical Devices

considered to pose potential risks great enough to warrant higher regulation; includes more sterilization equipment and chemical indicators; 501k required. eg syringes, hearing aids

Abigail Alliance v. Von Eschenbach outcome

court of appeals ruled in favor of AA, stating that US constitution protects rights of terminally ill to access treatment not approved by FDA (right of patients to do what they want to their bodies) ---- right to drugs in constitution overrules statutes Supreme court: Ruling overturned (8-2) Constitution does not guarantee right to access of unapproved medications by terminally ill. - No fundamental (implicit) right "deeply rooted i nour nationa's hx" for terminally ill access to experimental drugs. Encourages Alliance to petition congress; started policy discussions about IND drugs

biosimilars definition

highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. Biosimilars need to be expected to produce the same clinical results as the reference product without any greater risks; this is still controversial bc some say current science can't let us ensure that they're actually that similar - virtually impossible to guarantee that the protein is exactly the same every time - Purple Book contains biologics info

When can FDA may remove a drug from prescription only status?

if the limitations of the Rx status are not necessary for the protection of the public health

Is there a need to distinguish between a food and a drug when a supplier makes a therapeutic claim? Why?

if you make a therapeutic claim, you have to go through the drug approval process. so probably just maintain the food label. Less regulation

Violation of the FD&C Act does not require that the violator have known that its actions were illegal, or to have intended that its actions be illegal. Why should that be the case? Is it fair or just?

one is held accountable if the information even if you didn't know it's incorrect -> fair for pts but maybe not for the person who didn't know? - Under § 301(c), for example, a pharmacist who unknowingly and innocently receives an adulterated or misbranded drug and subsequently sells it to a consumer has violated the act. Exception: Section 303(c) - pharmacists have a "good faith" defense to adulteration and misbranding if they disclose the source of the adulterated or misbranded article upon request.

Educational Programs for healthcare professionals vs promotional activities

pharmaceutical manufacturers have sponsored and funded educational programs (usually for continuing education credit [CE]) for healthcare professionals. Concerns arise, however, when industry-supported programs are really product promotional activities disguised as educational programs. - The key to whether a manufacturer runs a risk of "misbranding" violations at educational programs is whether the program is truly "independent" and "non-promotional"

In NC, who governs physician dispensing? what about the disciplining power?

physician dispensing is governed by N.C.G.S. § 90-85.21, which requires that a dispensing physician register with the Board of Pharmacy and comply with all laws and regulations applicable to pharmacists. - the power to discipline physicians who fail to comply with such laws and regulations is vested in the North Carolina Board of Medicine, not the Board of Pharmacy.

Drug advertising to professionals

product is misbranded unless the manufacturer includes in all advertisements and other descriptive printed matter a "true statement" that includes: - established name of the drug - formula - a "brief summary" of information concerning side effects, contraindications, and effectiveness. This summary must present a "fair balance" between, on the one hand, side effects and contraindications and, on the other, effectiveness

Commercial Speech definition and regulation

promotional activities by product sellers, but gov can also regulate commercial activities so these have to be balanced. The government may regulate advertising that is false, misleading, or deceptive The government may regulate advertising for unlawful goods and services

How are generic drugs approved?

submit an 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 (cGMP)

Adulteration and misbranding violations are of a strict liability nature. What does that mean?

the commission of any of the listed offenses - adulteration or misbranding - violates the FDCA, regardless of the person's intentions or knowledge. - Under 302, the FDA can bring an injunctive action against the violator to cause it to cease its illegal activity.

unit-dose packaging adv

when a single dosage unit of a drug is prepackaged and prelabeled by the manufacturer or FDA-licensed packager for direct admin. Adv: reduce errors and diversion and permit the return of unused sealed doses

Does the FDA regulate prescription drug ads?

yes and it has a special office for this purpose called Office of Prescription Drug Promotion. The FTC (usually in collaboration with the FDA) regulates nonprescription drug advertising under the Federal Trade Commission Act

Does the FDA have statutory authority to require phase IV (or PMS) studies?

yes, the Congress conferred statutory to FDA to do so. Not following this requirement would be a violation of conditions of approval and the drug would be withdrawn from the market