Chapter 2

Emergency Use Authorization (EUA)

during public health emergencies, the fda may authorize the use of unapproved drugs or unapproved uses of approved drugs under certain conditions

Violations to the FDCA

- Misbranding - Adulteration - Tampering - Counterfeit drugs

New Pregnancy Class Warning Categories

- Drugs approved on or after 6/30/2015 - Pregnancy - Lactation (including amount of drug in breastmilk and potential effects to child) - Female and Male of Reproductive Potential

Cosmetic adulteration exemption

*Hair dyes that contain coal tar are EXEMPT from the adulteration and color additive provisions of the law

National Drug Code (NDC)

- A 10-digit number that indicates specifies the drug manufacturer, the drug product (drug strength, dosage form, and formulation), and the package size - First 4 number are labeler - Next 4 numbers are product code - Last 2 numbers are package code

Recalls

- A method of removing misbranded and/or adulterated products from the market to protect the public. Can be: voluntary by manufacturer, requested by FDA; Mandated by the FDA

Durham-Humphrey Amendment of 1951

- Allowed verbal prescriptions over phone and refills called in from physician's office, but not for electronic prescriptions

Kefauver-Harris Amendment of 1962

- Also known as the "Drug Efficacy Amendment". - passed in 1962, added the efficacy requirement for drug products, which was made retroactive to 1938. Drug products marketed prior to 1938 remained exempted. - Required drugs to be effective as well safe - Established GMP requirement - Transferred oversight of drug advertising from FTC to FDA - Strengthened clinical trials by requiring informed consent of research subjects and adverse drug reaction reporting

Individual patient access - IND

- An individual patient acting through a physician may request an IND (in phase II or III of the NDA process) for treatment of a serious disease or condition. - The FDA must determine that: - there is sufficient evidence of safety and efficacy to support the drug's use; and - the use will not interfere with clinical trials in support of marketing approval - Ex: Abigail Alliance decision rejected the plaintiffs' claim that they have a constitutional right to investigational drugs

Former Pregnancy Class Warning Categories

- Category A: No risk to fetus noted in well-controlled studies in pregnant women - Category B: No adequate studies in pregnant women but animal studies have not demonstrated fetal risk - Category C: Assess benefit v. risk to fetus before using- no adequate studies in pregnant women and animal studies show adverse effect - Category D: Noted risk of fetal harm however potential benefits may outweigh potential risks - Category X: Risks outweigh benefits. Fetal risk noted in animal and/or humans.

Classification of monograph ingredients

- Category I: generally recognized as safe, effective and not misbranded - Category II: not generally recognized as safe and effective or that are misbranded - Category III: insufficient data available to classify the ingredient

Dietary Supplements Containing Drugs

- DSHEA excludes an article as a DS if it was approved as a drug prior to it being marketed as a DS - Pharmanex case establishes that DSs cannot be specially manufactured to concentrate the natural drug ingredient

Nutritional or Structure/ Function Claims (DSHEA)

- DSHEA permits four types of nutritional support claims: - Benefiting a classical nutrient deficiency disease - Describing role of the DS in affecting the structure/function of the body - Characterizing the mechanism by which a DS acts to maintain the structure or function - Statements of general well-being - Claims must be substantiated as truthful and not misleading.

Unit Dose Packaging and Labeling requirements

- Established drug name of drug - Quantity of active ingredient per dosage unit - Expiration date - Lot or control # - Name and address of manufacturer, packer, and distributor * The guidance contains additional requirements for more than one dosage unit per unit dose container and requirements for the outer package - The number of dosage units contained, if more than one dosage, and the strength per dosage unit - The controlled substance symbol if required by the DEA - The statement "May be Habit Forming" where applicable*

Durham-Humphrey Amendment of 1951

- Exempted prescription drugs from the "adequate directions for use" label requirement so long as they contained "Caution Federal law prohibits dispensing without a prescription" ("Rx only")

FDA recall request

- FDA does not have authority to recall counterfeit, adulterated and misbranded drugs from the market - FDA limited authority to recall certain products such as medical devices, biological products, and foods, but not drugs. - *Seizure or injunction action if FDA request for recall is ignored

Dietary Supplement Health and Education Act of 1994 (DSHEA)

- FDA must regulate dietary supplements as food rather than drugs - the FDA cannot require pre - market approval for supplements - FDA is required to prove that a dietary supplement is unsafe before removing it from market

Consumer Product Tampering

- Federal offense to tamper with consumer products - Came from someone putting arsenic in Tylenol in 1980's

What Investigational drugs may be eligible for expanded access?

- For which a Phase 1 clinical trial has been completed: - That has not been approved or licensed by the FDA for any use - For which an application has been filed with the FDA or is under investigation in a clinical trial that is intended to form the primary basis of a claim of effectiveness in support of FDA approval and is the subject of an active investigational new drug application submitted to the FDA - Whose active development or production is ongoing, and that has not been discontinued by the manufacturer or placed on clinical hold by the FDA

Pregnancy Warnings

- Former system was letter category (A, B, C, X) - Labeling requirements regarding Pregnancy and Lactation

Current Good Manufacturing Practices (CGMPs)

- Good Manufacturing Practices ensure the drug is safe and meets quality and purity standards - assure proper design, monitoring, and control of manufacturing processes and facilities - assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. - Manufacturers must be registered with the FDA and are inspected once every two years by FDA - Non-compliance with CGMP regulations could result in FDA considering any drug the company makes is "adulterated", recalls or seizure of the drug or litigation.

Drug Efficacy Study Implementation (DESI) - Prescription and OTC drugs

- Implemented in 1968 in response to 1962 Kefauver-Harris Amendment that required all drugs be effective and safe. - Making the requirement retroactive for innovator and generics burdened the FDA. Several thousand drugs had been marketed between 1938-1962. - The FDA created the ANDA for generic drugs approved between 1938 and 1962. -The ANDA only requires evidence of bioequivalence and manufacturing methods rather than proof of safety and efficacy. - The U.S. Supreme Court ruled that generic drugs are new drugs and subject to FDA approval

Tampering

- Improper interference with the product for the purpose of making objectionable or unauthorized changes - FDA regulations require that certain OTC drugs, cosmetics and devices be manufactured in tamper-resistant packaging. - Tamper-resistant packaging provides visible evidence to a consumer that tampering occurred - Tamper resistant seal is different from child protective seal - Required that certain OTC drugs, and devices be manufactured in tamper resistant packaging

Drug vs Device

- Is the product intended to deliver drugs to the patient, but is not prefilled by the manufacturer (e.g. empty implantable infusion pumps)? - Is the drug component included solely to make the product safer (e.g. surgical drape impregnated with antimicrobial agents)? - Is the drug component intended to have a therapeutic effect (e.g. intrauterine contraceptive device that releases a hormone?

Adulteration of cosmetics

- It contains any poisonous or deleterious substances that may injure users - It contains filthy, putrid, or decomposed substance - It is prepared under unsanitary conditions - The container contains a substance that may contaminate the contents - It contains unsafe color additives but is not a hair dye*

Adequate information for use

- Labeling that prescription drugs must meet - Prescription drugs are intended to be administered under the supervision of medical practitioners and are exempt from "adequate direction for use" requirement

New Drug Approval

- No person may introduce a "new drug" into interstate commerce unless approved by the FDA. - before filing a NDA, evidence that the drug is safe and effective obtained from animal and clinical studies must be submitted - a sponsor must file an IND Application - The IND requires substantial information about the drug, its manufacturing and the experience and qualifications of clinical investigator

21st Century Cures Act and New Drug Approval

- Passed in 2016- designed to help accelerate medical product development and bring new innovations and advances to patients who need them faster and more efficiently - streamlining and adding flexibility to the drug development and approval process and creating a more patient-focused approach to the process - encourages the consideration of novel clinical trial designs and the incorporation of "real-world evidence" into the decision-making process

When is expanded access appropriate?

- Patient has a serious disease or condition, or whose life is immediately threatened by their disease or condition. - There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition. - Patient enrollment in a clinical trial is not possible. - Potential patient benefit justifies the potential risks of treatment. - Providing the investigational medical product will not interfere with investigational trials that could support a medical product's development or marketing approval for the treatment indication.

Risk Evaluation and Migration Strategies (REMS)

- Postmarket labeling - Postmarket drug safety information for patients and providers

MedWatch products

- Prescription and OTC medicines - Biologics - Medical devices - Special nutritional products - Cosmetics - Foods

Orphan Drug Act of 1983

- Provides incentives to promote research, approval, and marketing of drugs needed for the treatment of rare diseases.

Purple Book (FDA)

- Provides list of biological drug products and indicates which biological products can be interchanged

Pregnancy and Lactation Subheading requirements

- Risk summary - Clinical considerations - Data

Drug and/or Cosmetic

- Some products can be both drugs and cosmetics - "Ignorant, unthinking consumer" standard likely applied - A cosmetic can become a drug if the seller makes a health or structure/function claim

Durham-Humphrey Amendment of 1951

- Specifies the minimum info that a dispensed Rx label must contain - Expiration or beyond use dating on dispensed Rx label required pursuant to state laws

widespread patient treatment - IND

- The FDA will only approve treatment with an IND only if: - Serious or immediately life-threatening disease or condition - No comparable or satisfactory alternative therapy is available - Clinical trials for the IND are for the disease or condition - The sponsor is actively seeking approval of drug - For serious disease- there is sufficient evidence of safety and effectiveness for the use - For immediate life-threatening disease- there is reasonable basis that the drug may be effective and would not expose the patient to

Patent Considerations of ANDA

- The generic manufacturer must make one of four types of patent certifications. - A paragraph IV certification contends that the parent drug's patent is invalid or will not be infringed by the generic company. The ANDA applicant must notify patent holder. If holder sues, FDA is enjoined for 30 months, unless a court rules otherwise. The generic company receives 180 days of market exclusivity if it prevails under a paragraph IV certification.

Medical Device Amendment of 1976

- Under the FDCA 1938, the FDA had no authority to review medical devices for safety and efficacy before marketing. - In 1976 Congress amended FDCA to provide for more extensive regulation and authority regarding safety and efficacy of medical devices

Post - Market Surveillance: Phase 4

- Upon approval of the NDA, a manufacturer may legally distribute the drug into Interstate commerce - Manufacturer must establish and maintain a post-market records and reports - Serious adverse drug reactions must be submitted to the FDA and any new safety or efficacy information

Drug

- recognized by USP, official Homeopathic Pharmacopoeia of the US, or official National Formulary (NF) - intended for use in diagnosis, cute, mitigation, treatment, or prevention of disease - (Non - food) intended to affect structure or function of human body/ animals

dietary supplements

- a "dietary supplement" is a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients: (A) a vitamin; (B) a mineral; (C) an herb or other botanical; (D) an amino acid; (E) a dietary substance for use by man to supplement the diet by increasing the total dietary intake; or (F) a concentrate, metabolite, constituent, extract, or combination of any ingredient described in clause (A), (B), (C), (D), or (E)

Expanded Access/Compassionate Use

- a potential pathway for a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available. - The FDA enacted regulations permitting greater access by patients to investigational drugs. - Permits patients to seek access to experimental drugs even in phase 1 - Expands and clarifies the treatment use of experimental drugs - Clarifies and establishes the criteria for drug manufacturers to charge patients for investigational drugs - Several states have passed "right-to-try" laws - Passed by Congress in May 2018 - another way for patients who have been diagnosed with life-threatening diseases or conditions who have tried all approved treatment options and who are unable to participate in a clinical trial to access certain unapproved treatments.

Informed consent requirements

- a statement that the study involves research - process throughout the trial to protect the subjects of the study - an explanation of the purposes of the research and expected duration of the subject's participation - a description of the procedures to be followed, and identification of any procedures which are experimental - a description of any reasonably foreseeable risks or discomfort to the subject - a description of any benefits to the subject or to others which may reasonably be expected from the research - a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject

Expedited "Fast track: approval

- accelerated approval of new drugs for serious or life-threatening illnesses, sponsor must: -demonstrate the potential to address the unmet medical needs for the condition (Fast Track) or - demonstrate substantial improvement on a clinically significant endpoint compares to available therapy (Breakthrough Therapy) - Approval will be conditioned on the completion of post marketing or phase IV clinical studies to verify the drugs clinical benefits

Labeling

- all labels and other written, printed, or graphic matter upon any article or any of its containers or wrappers, or accompanying such article - includes the label and applies to the information "accompanying" the drug such as the package insert

device

- an instrument, apparatus, implement, machine, implant or other related article which is: - Recognized in the USP/NF; • Intended for diagnosis, cure, treatment or prevention; or • Intended to affect the structure of human or animal body, and which does not achieve its primary intended purpose by chemical action and is not dependent on metabolism to achieve its primary intended purpose.

Changes to Package Insert Requirements

- applies to NDA post 6/30/2006 - Reorganizes information to make it easily accessible, and less complex - Table of contents - Patient Counseling section - Online access FDA

Food

- articles used for food or drink for man or other animal - chewing gum, and - articles used for components of any such article

United States Pharmacopeia (USP)

- authoritative list of drugs, formulas, and preparations that sets uniform standards for drug manufacturing and dispensing - works closely with the FDA, but is a private organization

Recalls mandated by FDA

- authority only with regard to four products: infant formula, medical devices, biologic products, and tobacco products.

Medical Device Amendment of 1976 requirements

- classification of devices based on function - pre-market approval - compliance with good manufacturing practices (GMP - record and reporting requirements

New Drug Application (NDA)

- complete evaluation of the drug's safety and efficacy - Approval is based on proof of safety and efficacy, the manufacturing process, and risk-benefit ratio - Must include: - Details of drug chemistry - Preclinical trials - Manufacturing processes - Clinical trials - Packaging and labeling

Phase 4 clinical trials

- conducted after the drug has been marketed - to gather more info on the drug's effect in various populations and side effect profile

21st Century Cures Act and New Drug Approval

- creates or amends four pathways or programs for drugs that treat serious or life-threatening diseases that affect smaller populations or diseases with significant public health risks, including facilitating the development and approval pathway for genetically targeted drugs that meet unmet medical needs - Created a program for the approval of antimicrobial resistant drugs ("superbugs") for limited populations - Expanded orphan drug (drug that treats something very rare) program - Reauthorized the FDA voucher program FOR RARE PEDIATRIC DISEASES

Adulteration

- definition and explanation of adulteration - containing poisonous, insanitary, ingredients or manufactured without adequate controls - Filthy, putrid, or decomposed product - Containing a color additive which is unsafe - Strength, quality, or purity is different from official compendium

Adequate directions for use

- directions under which the layman can use a drug safely and for the purposes for which it is intended

label

- display of written, printed, or graphic matter upon the immediate container of any article

Abbreviated New Drug Application (ANDA)

- refers to the previously approved NDA (the "listed drug") and relies on the safety and effectiveness findings for the listed drug product. - The FDA publishes patent information on approved drug products in the Agency's publication Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book."

Food and Drug Administration Amendments Act of 2007 (FDAAA)

- empowered the FDA to require manufacturers to conduct phase IV clinical trials when adverse event reporting or active surveillance is inadequate - required the FDA to develop and maintain a website for patients and providers including labeling, safety information, REMS, guidance documents, etc. - Post marketing labeling: The FDAAA gave the FDA the authority to require manufacturers to add safety information or warnings postmarket. - established Sentinel Initiative - granted the FDA authority to require REMS as a condition for approval of an NDA or postmarket when the FDA believes it necessary to ensure benefits outweigh risks. - Under REMS authority, the FDA can require a variety of procedures ranging from Medication Guides to limiting the drug to specified settings for dispensing - requires PHARMACIES to provide patients with the MedWatch number and a statement about reporting side effects.

Prescription Drug Marketing Act go 1987

- established requirements for prescription drug sample distributions and prohibits resale of pharmaceuticals by hospitals and other healthcare entities to other businesses

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

- facilitated the approval process of generic drugs while affording patent extension to innovator drug products - Created a statutory generic drug approval process - created automatic approval for generic drugs by eliminating submission to FDA - Established the abbreviated new drug applications (ANDA) process. - the amendment allowed for greater generic competition - Enhanced protection for innovators - Provided certain non-patent exclusivities, including Orphan drug exclusivity

Phase 1 clinical trials

- first in human use; small group of people - evaluate the drug's safety; determine a safe dosage range and identify the drug's side effects

Class 2 Medical device

- general controls alone are insufficient to ensure safety and effectiveness. Must meet specific performance standards established by the FDA before marketing approval granted by FDA. Ex) insulin syringes, infusion pumps, thermometers, tampons, electric heating pads

Supplemental New Drug Application (SNDA)

- generally required when a manufacturer makes any change in an approved drug or in its production - three categories of SNDA - A "change being effected (CBE)" SNDA allows the sponsor to make the change before FDA approval and is important for labeling changes

Female and Male Reproductive Potential subsection requirements

- information about pregnancy testing, contraception and infertility as related to the drug

Package Insert

- intended to be read by healthcare professionals - pamphlet that must accompany a drug product - contains scientific and medical info needed for safe and effective use of the drug

cosmetics

- intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and - intended for use as a component of any such articles; except that such term shall not include soap.

Informed Consent

- intended to protect the human research subjects - required for patients participation in phase 1 - 3 clinical trials (with some exceptions, such as emergencies) and must be in writing for phase I and II trials.

Health of Disease Claims

- label must contain a disclaimer - DSHEA only permits DS manufacturers to make health claims if either the FDA approves the claim by regulation or by the significant scientific agreement test

Misbranding

- label or labeling of a product that is false or misleading - Label or Labeling does not include required elements - required label or labeling is not prominently displayed - it is an imitation of another drug - packaging does not conform to Poison Prevention Packaging Act

black box warning

- labeling requirement that the FDA may require - a warning that a drug may lead to death or serious injury - may be required during the NDA review/ approval process if risks are known after approval - warning of the special problem in the package insert within a prominently displayed box - not a contraindication, but risk assessment

Phase 2 clinical trials

- large group of people to evaluate drug's effectiveness and to further evaluate the drug's safety

Phase 3 clinical trials

- larger groups of people to confirm drug's effectiveness, monitor side effects - compare to other commonly used treatments - collect info that will allow the drug or treatment to be used safely

Class 1 Medical Device

- least harm to users, general controls are adequate to ensure safety and effectiveness. General controls include registering facility with FDA, listing their products with the FDA, following GMP, maintain records and reports and premarket notification in some cases. Ex) scissors, needles, stethoscope, toothbrushes

FDA Compliance document

- list the required label elements for the unit dose container* (solid or liquid dosage forms)

Food and Drug Administration Modernization Act of 1997

- made it discretionary to include habit forming warning on label; however, the manufacturer must still adequately describe the habit-forming characteristics of the drug in the "Drug Abuse and Dependence section of the package insert

cosmetics approval

- no premarket approval or conformance with GMP - manufacturers must substantiate product safely - FDA may remove if misbranded, adulterated or a health hazard - must be labeled with list of ingredients in descending order of predominance and appropriated warnings

Pure Food and Drug Act of 1906

- profited the adulteration and misbranding of foods and drugs in interstate commerce - required drugs to meet USP/ NF standards - misbranding provision only prevented false claims regarding the drug's ID , but not false or misleading efficacy claims - did NOT give FDA authority to ban unsafe drugs

Food, Drug, and Cosmetic Act of 1938 (FD&C Act)

- prompted by the Sulfanilamide elixir tragedy of 1937 - no New Drug can be approved until proven safe for use under conditions described on the label and approved by FDA - labels must contain adequate directions for use and warning - expanded to cover cosmetics

Biologics

- replicate natural substances such as enzymes, antibodies, or hormones in out bodies. - FDA regulates a wide range of biologics, such as - blood and blood components - gene therapy products - human tissue and cellular products used in transplantation - Vaccines - Allergy extracts

Class 3 Medical Device

- require pre-market approval because the devices are life-supporting or life-sustaining or present potential unreasonable risk of illness or injury. Ex) implantable pacemakers and breast implants

Investigation New Drug (IND)

- requires substantial information about the drug, its manufacturing and the experience and qualifications of clinical investigator - the drug must be safe effective in animal trials. The IND is required before clinical trials may begin - allows you to put drug into interstate commerce (1st step in clinical trial process)

Functions of FDA

- rulemaking - issue guidance documents - incorporate advice from standing advisory committee of outside experts

Food and Drug Administration (FDA)

- section of the Department of Health and Human Services - lead by a Commissioner, who is appointed by the President (w/ Senate approval)

Dietary Supplements: Safety Issues

- the FDA can only remove a DS on the basis of the product being adulterated, defined as presenting "significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labeling" - Example: ephedrine alkaloid DS got recalled FDA - The Dietary Supplement and Nonprescription Drug Consumer Protection Act requires manufacturers to report serious adverse events.

MedWatch

- voluntary reporting system maintained by the FDA that allows healthcare professionals to report serious adverse events, including serious drug side effects, product use errors, product quality problems

Food and Drug Administration Modernization Act of 1997 - IND Drugs for Treatment

- widespread patient treatment - individual patient access - expanded access

Misbranding of cosmetics

-Cosmetics may be misbranded if its labeling is false, misleads the consumer, or lacks the required information, or if its label information is not clear enough to be read by the ordinary consumer

Homeopathic Pharmacopoeia of the United States (HPUS)

-Published by a PRIVATE organization or convention -Regularly updated information on homeopathic products or remedies - Pursuant to FDCA, if a drug is recognized in USP or HPUS, the drug product must meet all standards of the compendia.

Efficacy Review of OTC Medications

-The efficacy requirement applied retroactively to all drugs marketed after 1938 - included generics and over-the-counter (OTC) medication -Unlike Prescription drugs, OTC's were not reviewed individually -Advisory review panels of qualified experts consider drugs by class -Products were classified by rulemaking rather than case-by-case approval

Durham-Humphrey Amendment of 1951

-created a distinction between "OTC" and "Legend Drugs" (prescription)

Pearson v. Shalala

-held that DS manufacturers could make health claims not approved by the FDA provided they are not false or misleading and accompanied by a disclaimer - FDA now allows qualified and unqualified health claims

Prescription Drug Fee User Act of 1992

allowed FDA to collect fees from drug manufacturers to fund the new drug approval process

Sentinel Initiative

new FDA system for post-market surveillance and to detect early signs of a drug's risk

Drug Fact Paneling

o Active ingredients, including dosage unit and quantity per unit o Purpose o Uses o Directions o Inactive ingredients (alphabetical order) o Telephone Number for Consumer Questions

Non - Prescription Drug Labeling requirements

o Identity, including established name o Name and address of manufacturer, packer, and distributor o Cautions and warning to protect the consumer (Drug Fact Panel) o "Adequate Directions for Use"

Prescription Drug Labels and Labeling requirements

o Name and address of manufacturer, packer, and distributor o Established name of drug product o Active ingredients, including quantity and proportion of each o Inactive Ingredient Name(s) (w/ some exception) if not oral o Statement of identity (generic and proprietary names) o Statement of recommended or usual dosage or reference to package insert o Quantity- Weight and Measure (e.g. 75mg) o Quantity- Container (e.g. #100 capsules) o Route of administration (except if oral) o Lot or control # o Expiration date (unless exempted) o "Rx" only or Caution: "Federal law prohibits dispensing without a prescription" o Direction to RPh regarding container type for dispensing (e.g. "light resistance bottle")

Adequate Labeling (directions for use) must include

o Quantity or dosage for each intended use and for persons of different ages and physical conditions o Frequency of administration or application o Duration of use o Time of administration or use o Route of administration o Necessary preparation instructions (e.g. shake well)

Adequate Information for use requirements

o indications, including all purposes for which it is advertised or represented o side effects o Dosages o routes, methods, and frequency and duration of administration o Other warning/precautions required to administer, prescribe, dispense the drug safely

Classifications of Recalls

• Class I: Reasonable probability that product will cause serious adverse health effects or death (ex: Losartan) • Class II: Product may cause temporary or medically reversible adverse health effects, but serious adverse effects are remote • Class III: Product unlikely to cause adverse health effects