mass pharmacy law 2014

Federal and MassachusettsPharmacy Law Study Guide

For the Standardized Pharmacy Law Exam

2014 Version

Note: In this study guide, italics denotes language quoted verbatim from the law.The source of the cited law has been provided when appropriate. A series ofdots (. . .) within an italicized quote signifies that language has been editoriallydeleted because it is deemed not sufficiently relevant to the objectives of thisstudy guide. Because the language of the law as quoted in this study guide istaken out of context, and has been edited for purposes of educational clarity, thestudy guide should not be used as a reference by one who is seeking a completeunderstanding of all laws. For specific legal advice, pharmacists and pharmacystudents should refer to the complete law at a library, or seek competent legalcounsel.

The materials provided in this study guide are updated annually. This studyguide utilizes various resources, including federal and state websites, which mayonly update materials periodically. Changes in the law may occur prior to the nextupdated version. Purchasers are advised to review the online federal and stateresources listed in the Study Guide for the most up-to-date changes. The lawsreviewed in this study guide are not a complete listing of all federal and statelaws and only provide a review. For a complete listing of all state laws, refer tothe website(s) provided in the state materials of this study guide. For a completelisting of all federal laws, refer to the FDA website athttp://www.fda.gov/opacom/laws/, and to the DEA website athttp://www.deadiversion.usdoj.gov/21cfr/index.html.

Disclaimer: The materials in this document are intended for general information purposes only,and are not intended to provide, and do not constitute, legal advice. Persons who need legal

advice should contact an attorney.

Copyright 2014, RxLaw.org, Inc. All Rights Reserved.

Index

Chapter 1: The Food & Drug Administration................................4

Chapter 2: Federal Drug Control Law.........................................17

Chapter 3: Federal Controlled Substance Law.............................65

Chapter 4: The Drug Enforcement Administration....................104

Chapter 5: Massachusetts Statutes ............................................157

Chapter 6: Massachusetts Administrative Rules .......................188

Chapter 7: Sample Pharmacy Law Exam ..................................297

Copryright 2014, RxLaw.org, Inc. All Rights Reserved

Federal Pharmacy Law Review

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Chapter 1 : The Food and Drug Administration

The Federal Food and Drug Administration (FDA) is one of the most highly regarded federal agencies. The FDA isan agency within the Department of Health and Human Services and consists of numerous centers, including:

1. Center for Biologics Evaluation and Research (CBER). CBER is the Center within FDA that regulates biologi-cal products for human use under applicable federal laws, including the Public Health Service Act and the FederalFood, Drug and Cosmetic Act. CBER protects and advances the public health by ensuring that biological productsare safe and effective and available to those who need them. CBER also provides the public with information topromote the safe and appropriate use of biological products. CBER's mission is to protect and enhance the publichealth through the regulation of biological and related products including blood, vaccines, allergenics, tissues, andcellular and gene therapies.

2. Center for Devices and Radiological Health (CDRH). CDRH is responsible for regulating firms who manufac-ture, repackage, relabel, and/or import medical devices sold in the United States. In addition, CDRH regulates radi-ation-emitting electronic products (medical and non-medical) such as lasers, x-ray systems, ultrasound equipment,microwave ovens and color televisions.

3. Center for Drug Evaluation and Research (CDER). CDER performs an essential public health task by makingsure that safe and effective drugs are available to improve the health of people in the United States. CDER regu-lates over-the-counter and prescription drugs, including biological therapeutics and generic drugs. The Center is aconsumer watchdog in America's healthcare system. CDER's best-known job is to evaluate new drugs before theycan be sold. The Center's review of new drug applications not only prevents quackery, but it provides doctors andpatients with the information they need to use medicines wisely.

4. Center for Food Safety and Applied Nutrition (CFSAN). CFSAN, in conjunction with FDA field staff, is re-sponsible for promoting and protecting the public's health by ensuring that the nation's food supply is safe, sani-tary, wholesome, and honestly labeled, and that cosmetic products are safe and properly labeled. CFSAN providesservices to consumers, domestic and foreign industry and other outside groups regarding field programs; agencyadministrative tasks; scientific analysis and support; and policy, planning and handling of critical issues related tofood and cosmetics.

5. The Center for Tobacco Products (CTP). CTP oversees the implementation of the Family Smoking Preventionand Tobacco Control Act. Some of the Agencys responsibilities under the law include setting performance stan-dards, reviewing premarket applications for new and modified risk tobacco products, requiring new warning labels,and establishing and enforcing advertising and promotion restrictions.

6. The Center for Veterinary Medicine (CVM). CVM regulates the manufacture and distribution of food additivesand drugs that will be given to animals. These include animals from which human foods are derived, as well asfood additives and drugs for pet (or companion) animals. CVM is responsible for regulating drugs, devices, andfood additives given to, or used on, over one hundred million companion animals, plus millions of poultry, cattle,swine, and minor animal species. (Minor animal species include animals other than cattle, swine, chickens, tur-keys, horses, dogs, and cats.)

7. The National Center for Toxicological Research (NCTR). NCTR is the FDA's internationally recognized re-search center. NCTR, in partnership with researchers from elsewhere in the FDA, other government agencies, ac-ademia, and industry, provides innovative technology, methods development, vital scientific training, and technicalexpertise. The unique scientific expertise of NCTR is critical in supporting FDA product centers and their regulato-ry roles.



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In addition to being trusted with safeguarding the safety, effectiveness and integrity of the nations drug supply, theagency has had authority since 1948 to regulate the act of dispensing by a pharmacist. Although technically limited to theregulation of interstate commerce, the courts have consistently held that the dispensing of a drug by a pharmacist to a pa-tient, even though the act occurs entirely within a state, is an act that is in interstate commerce. Since the FDA has an impor-tant role in the regulation and implementation of federal laws, pharmacy practitioners should have a basic understanding ofthe role of the FDA. The following provides information, including excerpts from FDA publications, describing the function-ing of the agency. For additional information about the FDA, visit www.fda.gov.

A. CDER: The Consumer Watchdog for Safe and Effective DrugsAmerican consumers benefit from having access to the safest and most advanced pharmaceutical system in the world. CDERensures that drugs, both brand-name and generic, work correctly and that their health benefits outweigh their known risks.This responsibility includes products that many consumers usually do not associate as drugs, such as fluoride toothpaste, dan-druff shampoos and sunscreens. CDER carefully evaluates the benefits and risks of drugs and ensures that consumers haveaccess, as quickly as possible, to promising new treatments. The center oversees the research, development, manufacture andmarketing of drugs. CDER ensures truth in advertising for prescription drugs and monitors the use of marketed drugs for un-expected health risks. If unexpected risks are detected after approval, CDER takes action to inform the public, change a drug'slabel, or--if necessary--remove a product from the market.

CDER has multiple Offices and Divisions, including: Office of New Drugs; Office of Nonprescription Products; Office ofOncology Drug Products; Office of Pharmaceutical Science; Office of Biotechnology Products; Office of Generic Drugs; Of-fice of New Drug Quality Assessment; Office of Testing and Research; Office of Surveillance and Epidemiology (formerlyOffice of Drug Safety); and Division of Drug Information.

Prescription DrugsPrescription medicines must be administered under a doctor's supervision or require a doctor's authorization for purchase.There are several reasons that medicines are required to be sold by prescription. The disease or condition may be serious andrequire a doctor's management. The same symptoms can be caused by different diseases that only a doctor can diagnose. Thedifferent causes may require different medicines. Some medicines can be dangerous when used to treat the wrong diseases,and some drugs are abused.

OTC DrugsOver-the-counter (OTC) drugs play an increasingly vital role in America's health care system. OTC drug products are thosedrugs that are available to consumers without a prescription. There are more than 80 therapeutic categories of OTC drugs,ranging from acne drug products to weight control drug products. As with prescription drugs, CDER oversees OTC drugs toensure that they are properly labeled and that their benefits outweigh their risks. OTC drugs generally have these characteris-tics:

their benefits outweigh their risks the potential for misuse and abuse is low consumer can use them for self-diagnosed conditions they can be adequately labeled health practitioners are not needed for the safe and effective use of the product

Generic DrugsA generic drug is a chemical clone of a drug sold under a brand name. There are generic versions of both prescription andOTC medicines. For example, ibuprofen is the generic name of the anti-inflammatory drug sold under the brand namesMotrin or Advil. The biggest difference between a generic drug and a brand-name drug is usually price. A generic drug oftencosts about 30 percent less than the brand-name drug. Widespread use of generics helps control medical costs and insurancepremiums.The FDA works with pharmaceutical companies to assure that all drugs marketed in the United States meet specifications foridentity, strength, quality, purity, and potency. Before approving a generic drug product, CDER requires many rigorous testsand procedures to assure that the generic drug can be substituted for the brand name drug. CDER bases evaluations of substi-



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tutability or "therapeutic equivalence" for generic drugs on scientific evaluations. By law, generic drug products must containthe identical amounts of the same active drug ingredient as the brand name product. Drug products evaluated as"therapeutically equivalent" can be expected to have equal effect and no difference when substituted for the brand name prod-uct. FDA considers drug products to be substitutable if they meet the criteria of therapeutic equivalence, even though the ge-neric drug may differ in certain other characteristics (e.g., shape, flavor, or preservatives).

B. The FDA's Drug Review Process: Ensuring Drugs Are Safe and EffectiveThe path a drug travels from a lab to your medicine cabinet is usually long, and every drug takes a unique route. Often, a drugis developed to treat a specific disease. An important use of a drug may also be discovered by accident. For example, Retrovir(zidovudine, also known as AZT) was first studied as an anti-cancer drug in the 1960s with disappointing results. It wasn'tuntil the 1980s that researchers discovered the drug could treat AIDS, and the Food and Drug Administration approved thedrug, manufactured by GlaxoSmithKline, for that purpose in 1987. Most drugs that undergo preclinical (animal) testing nevereven make it to human testing and review by the FDA. The drugs that do must undergo the agency's rigorous evaluation pro-cess, which scrutinizes everything about the drug--from the design of clinical trials to the severity of side effects to the condi-tions under which the drug is manufactured.

Investigational New Drug ApplicationIn many ways, the investigational new drug (IND) application is the result of a successful preclinical development program.The IND is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials(human trials). During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product isreasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial de-velopment. When a product is identified as a viable candidate for further development, the sponsor then focuses on collectingthe data and information necessary to establish that the product will not expose humans to unreasonable risks when used inlimited, early-stage clinical studies.

The IND is not an application for marketing approval. Rather, it is a request for an exemption from the Federal statute thatprohibits an unapproved drug from being shipped in interstate commerce. Current Federal law requires that a drug be the sub-ject of an approved marketing application before it is transported or distributed across state lines. Because a sponsor willprobably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from thatlegal requirement. The IND is the means through which the sponsor technically obtains this exemption from the FDA; how-ever, its main purpose is to detail the data that provide documentation that it is indeed reasonable to proceed with certain hu-man trials with the drug.

Treatment Investigational New DrugTreatment Investigational New Drugs are used to make promising new drugs available to desperately ill patients as early inthe drug development process as possible. FDA will permit an investigational drug to be used under a treatment IND if thereis preliminary evidence of drug efficacy and the drug is intended to treat a serious or life-threatening disease, or if there is nocomparable alternative drug or therapy available to treat that stage of the disease in the intended patient population. In addi-tion, these patients are not eligible to be in the definitive clinical trials, which must be well underway, if not almost finished.

An immediately life-threatening disease means a stage of a disease in which there is a reasonable likelihood that death willoccur within a matter of months or in which premature death is likely without early treatment. For example, advanced casesof AIDS, herpes simplex encephalitis, and subarachnoid hemorrhage are all considered to be immediately life-threatening dis-eases. Treatment INDs are made available to patients before general marketing begins, typically during Phase 3 studies.Treatment INDs also allow FDA to obtain additional data on the drug's safety and effectiveness.

New Drug ApplicationThis is the formal step a drug sponsor takes to ask that the FDA consider approving a new drug for marketing in the UnitedStates. A new drug application (NDA) includes all animal and human data and analyses of the data, as well as information



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about how the drug behaves in the body and how it is manufactured. When an NDA comes in, the FDA has 60 days to decidewhether to file it so that it can be reviewed. The FDA can refuse to file an application that is incomplete. For example, somerequired studies may be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center forDrug Evaluation and Research (CDER) expects to review and act on at least 90 percent of NDAs for standard drugs no laterthan 10 months after the applications are received. The review goal is six months for priority drugs. There is also continuousinteraction throughout the review process. For example, over roughly six years, the sponsor, Merck Research Laboratories ofWest Point, Pa., and the FDA had several face-to-face meetings and about 28 teleconferences regarding the asthma drug Sin-gulair (montelukast sodium).

Reviewing ApplicationsThough FDA reviewers are involved with a drug's development throughout the IND stage, the official review time is thelength of time it takes to review a new drug application and issue an action letter, an official statement informing a drug spon-sor of the agency's decision. Once a new drug application is filed, an FDA review team--medical doctors, chemists, statisti-cians, microbiologists, pharmacologists, and other experts--evaluates whether the studies the sponsor submitted show that thedrug is safe and effective for its proposed use. No drug is absolutely safe; all drugs have side effects. "Safe" in this sensemeans that the benefits of the drug appear to outweigh the risks.

The review team analyzes study results and looks for possible issues with the application, such as weaknesses of the studydesign or analyses. Reviewers determine whether they agree with the sponsor's results and conclusions, or whether they needany additional information to make a decision.Each reviewer prepares a written evaluation containing conclusions and recommendations about the application. These evalu-ations are then considered by team leaders, division directors, and office directors, depending on the type of application.

Reviewers receive training that fosters consistency in drug reviews, and good review practices remain a high priority for theagency. Sometimes, the FDA calls on advisory committees made up of outside experts, who help the agency decide on drugapplications. Whether an advisory committee is needed depends on many things. Considerations would be if it's a drug thathas significant questions, if it's the first in its class, or the first for a given indication. Generally, the FDA takes the advice ofadvisory committees, but not always.

FDA Process for Responding to Drug ApplicationsAs of August, 2008, CDER no longer issued "approvable" or "not approvable" letters when a drug application is not ap-proved. Instead, CDER now issues a "complete response" letter at the end of the review period to let a drug company know ofthe agency's decision on the application. This approach will help the FDA adopt a more consistent and neutral way of con-veying information to a company when the FDA cannot approve a drug application in its present form. Taking the place of"approvable" and "not approvable" letters, a "complete response" letter will be issued to let a company know that the reviewperiod for a drug is complete and that the application is not yet ready for approval. The letter will describe specific deficien-cies and, when possible, will outline recommended actions the applicant might take to get the application ready for approval.

Drug Review Steps Preclinical (animal) testing. An investigational new drug application (IND) outlines what the sponsor of a new drug proposes for human testing in

clinical trials. Phase 1 studies (typically involve 20 to 80 people). Phase 2 studies (typically involve a few dozen to about 300 people). Phase 3 studies (typically involve several hundred to about 3,000 people). The pre-NDA period, just before a new drug application (NDA) is submitted. A common time for the FDA and drug

sponsors to meet. Submission of an NDA is the formal step asking the FDA to consider a drug for marketing approval. After an NDA is received, the FDA has 60 days to decide whether to file it so it can be reviewed. If the FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's research on the drug's safety and ef-

fectiveness.



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The FDA reviews information that goes on a drug's professional labeling (information on how to use the drug). The FDA inspects the facilities where the drug will be manufactured as part of the approval process. FDA reviewers will issue a response letter to let a drug company know the agencys decision on the application.

The Role of User FeesSince the Prescription Drug User Fee Act (PDUFA) was passed in 1992, thousands of drugs and biologics have come to themarket, including new medicines to treat cancer, AIDS, cardiovascular disease, and life-threatening infections. PDUFA hasallowed the Food and Drug Administration to bring access to new drugs as fast or faster than anywhere in the world, all whilemaintaining the same thorough review process. Under PDUFA, drug companies agree to pay fees that boost FDA resources,and the FDA agrees to time goals for its review of new drug applications. Along with supporting increased staff, drug userfees help the FDA upgrade resources in information technology. The agency has moved toward an electronic submission andreview environment, now accepting more electronic applications and archiving review documents electronically.

The goals set by PDUFA apply to the review of original new human drug and biological applications, resubmissions of origi-nal applications, and supplements to approved applications. The second phase of PDUFA, known as PDUFA II, was reautho-rized in 1997 and extended the user fee program through September 2002. PDUFA III, which extended to Sept. 30, 2007, wasreauthorized in June 2002. PDUFA IV was reauthorized in September 2007 and extends an additional 5 years. PDUFA al-lows the FDA to spend some user fees to increase surveillance of the safety of medicines during their first two years on themarket, or three years for potentially dangerous medications. It is during this initial period, when new medicines enter intowide use, that the agency is best able to identify and counter adverse side effects that did not appear during the clinical trials.In addition to setting time frames for review of applications, PDUFA sets goals to improve communication and sets goals forspecific kinds of meetings between the FDA and drug sponsors. It also outlines how fast the FDA must respond to requestsfrom sponsors. Throughout a drug's development, the FDA advises sponsors on how to study certain classes of drugs, how tosubmit data, what kind of data are needed, and how clinical trials should be designed.

C. Inside Clinical Trials: Testing Medical Products in PeopleWhat Is a Clinical Trial?Clinical trials, also known as clinical studies, test potential treatments in human volunteers to see whether they should be ap-proved for wider use in the general population. A treatment could be a drug, medical device, or biologic, such as a vaccine,blood product, or gene therapy. Potential treatments, however, must be studied in laboratory animals first to determine poten-tial toxicity before they can be tried in people. Treatments having acceptable safety profiles and showing the most promiseare then moved into clinical trials.

Although "new" may imply "better," it is not known whether the potential medical treatment offers benefit to patients untilclinical research on that treatment is complete. Clinical trials are an integral part of new product discovery and developmentand are required by the Food and Drug Administration before a new product can be brought to the market.

The FDA is committed to protecting the participants of clinical trials, as well as providing reliable information to those inter-ested in participating. Recently, unethical behavior on the part of some researchers has shaken the public trust and promptedthe federal government to establish regulations and guidelines for clinical research to protect participants from unreasonablerisks.

Although efforts are made to control risks to clinical trial participants, some risk may be unavoidable because of the uncer-tainty inherent in clinical research involving new medical products. It's important, therefore, that people make their decisionto participate in a clinical trial only after they have a full understanding of the entire process and the risks that may be in-volved.

Why Participate in a Clinical Trial?People volunteer to participate in clinical trials for different reasons. Some volunteer because they want to help advance med-ical knowledge. Others have tried all available treatments for their condition without success. In a 2000 Harris Poll of cancer



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clinical trial participants, 76 percent of the respondents said they participated because they believed that the trial offered thebest quality of care for their disease. Helping other people and receiving more and better attention for their own specific dis-ease were other reasons cited. People should not, however, be tempted to enroll in a clinical trial simply because a potentialtreatment is being offered free during a study, or because of the promise of money. This could lead to people overlookingknown risks.

Who Can Participate?It's important to test medical products in the people they are meant to help. In the past, most new drug testing had been doneon white men. Groups such as women, blacks, and Hispanics often were not adequately represented. It's important to testmedical products in a wide variety of people because drugs can work differently in people of various ages, races, ethnicity,and gender. The FDA seeks to ensure that people from many different groups are included in clinical trials.

Trial guidelines, or eligibility requirements, are developed by the researchers and usually include criteria for age, sex, typeand stage of disease, previous treatment history, and other medical conditions. Some trials involve people with a particularillness or condition to be studied, while others seek healthy volunteers. Inclusion or exclusion criteria--medical or social stan-dards used to determine whether a person may or may not be allowed to enter a clinical trial--help identify appropriate partic-ipants and help to exclude those who may be put at risk by participating in a trial. Volunteering for a clinical trial is noguarantee of acceptance. Similarly, there's no guarantee that an individual in a clinical trial will receive the drug or medicalproduct being studied.

What Happens in a Clinical Trial?Every clinical trial is carefully designed to answer certain research questions. A trial plan called a protocol maps out whatstudy procedures will be done, by whom, and why. Products are often tested to see how they compare to standard treatmentsor to no treatment. The FDA often provides extensive technical assistance to researchers conducting clinical trials, helpingthem design better trials that can characterize effects of a new product more efficiently, while reducing risks to those partici-pating in the trials. The clinical trial team includes doctors and nurses, as well as other health care professionals. This teamchecks the health of the participant at the beginning of the trial and assesses whether that person is eligible to participate.Those found to be eligible--and who agree to participate--are given specific instructions, and then monitored and carefullyassessed during the trial and after it is completed.

Done at hospitals and research centers around the country, clinical trials are conducted in phases. Phase 1 trials try to deter-mine dosing, document how a drug is metabolized and excreted, and identify acute side effects. Usually, a small number ofhealthy volunteers (between 20 and 80) are used in Phase 1 trials. Phase 2 trials include more participants (about 100-300)who have the disease or condition that the product potentially could treat. In Phase 2 trials, researchers seek to gather furthersafety data and preliminary evidence of the drug's beneficial effects (efficacy), and they develop and refine research methodsfor future trials with this drug. If the Phase 2 trials indicate that the drug may be effective--and the risks are considered ac-ceptable, given the observed efficacy and the severity of the disease--the drug moves to Phase 3. In Phase 3 trials, the drug isstudied in a larger number of people with the disease (approximately 1,000-3,000). This phase further tests the product's ef-fectiveness, monitors side effects and, in some cases, compares the product's effects to a standard treatment, if one is alreadyavailable. As more and more participants are tested over longer periods of time, the less common side effects are more likelyto be revealed. Sometimes, Phase 4 trials are conducted after a product is already approved and on the market to find outmore about the treatment's long-term risks, benefits, and optimal use, or to test the product in different populations of people,such as children. Phase 2 and Phase 3 clinical trials generally involve a "control" standard. In many studies, one group of vol-unteers will be given an experimental or "test" drug or treatment, while the control group is given either a standard treatmentfor the illness or an inactive pill, liquid, or powder that has no treatment value (placebo). This control group provides a basisfor comparison for assessing effects of the test treatment. In some studies, the control group will receive a placebo instead ofan active drug or treatment. In other cases, it is considered unethical to use placebos, particularly if an effective treatment isavailable. Withholding treatment (even for a short time) would subject research participants to unreasonable risks.The treatment each trial participant receives is often decided by a process called randomization. This process can be com-pared to a coin toss that is done by computer. During clinical trials, no one likely knows which therapy is better, and random-ization assures that treatment selection will be free of any preference a physician may have. Randomization increases the



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likelihood that the groups of people receiving the test drug or control are comparable at the start of the trial, enabling compar-isons in health status between groups of patients who participated in the trial. In conjunction with randomization, a featureknown as blinding helps ensure that bias doesn't distort the conduct of a trial or the interpretation of its results. Single-blind-ing means the participant does not know whether he or she is receiving the experimental drug, an established treatment forthat disease, or a placebo. In a single-blinded trial, the research team does know what the participant is receiving. A double-blinded trial means that neither the participant nor the research team knows during the trial which participants receive the ex-perimental drug. The patient will usually find out what he or she received at a pre-specified time in the trial.

What Are the Risks?Some treatments being studied can have unpleasant, or even serious, side effects. Often these are temporary and end when thetreatment is stopped. Others, however, can be permanent. Some side effects appear during treatment, and others may notshow up until after the study is over. The risks depend on the treatment being studied and the health of the people participat-ing in the trial. All known risks must be fully explained by the researchers before the trial begins. If new risk information be-comes available during the trial, participants must be informed.

How Are People Protected?Most clinical trials are federally regulated with built-in safeguards to protect participants. Today, the Office for Human Re-search Protections (OHRP) in the Department of Health and Human Services (HHS) leads the department's programs for theprotection of human research participants and oversees human protection in HHS-funded research. The FDA has authorityover clinical trials for drug, biologic, and medical device products regulated by the agency. This authority includes studiesthat are HHS-funded (with joint oversight by the FDA and the OHRP), as well as studies that are solely funded by industry orby private parties. Many clinical trials are not subject to FDA regulation but are monitored by the institution sponsoring thetrial, such as a hospital. To help protect the rights and welfare of volunteers and verify the quality and integrity of data sub-mitted for review, the FDA performs inspections of clinical trial study sites and anyone involved in the research. The qualityof clinical trials has improved markedly since the agency started inspecting in 1977. Between the FDA, other governmentagencies, the review by institutional review boards, the required monitoring of studies by industry or private sponsors, andthe required oversight and reporting by investigators and their staff, a lot of people are looking out for the research subject'ssafety.

What Is Informed Consent?The FDA requires that potential participants be given complete information about the study. This process is known as"informed consent," and it must be in writing. The informed consent process provides an opportunity for the researcher andpatient to exchange information and ask questions. Patients invited to enter a trial are not obligated to join, but can consent toparticipate if they find the potential risks and benefits acceptable. A consent form must be signed by the participant prior toenrollment and before any study procedures can be performed. Participants also have the right to leave a study at any time. Atthe same time, people need to know that circumstances may arise under which their participation may be terminated by theresearcher, without their consent. For example, sometimes it becomes evident early on that a trial is not working and re-searchers know they are not going to get enough meaningful information to make continuation worthwhile. In addition, if anunexpected change occurs in the health status of a participant, such as toxic effects or sudden kidney problems that may havedeveloped, it would not be in the best interest of the patient to continue, and certainly not consistent with what the investiga-tor is trying to study. In any case, the circumstances must be described in the consent document.

Where to Get Information on Clinical TrialsIt is often difficult for patients to learn about opportunities to participate in clinical trials. Doctors and patient advocacygroups can be valuable resources for patients in search of clinical trial information. Newspapers, particularly in large cities,often carry clinical trial recruitment advertisements. A call to the relevant department at nearby university medical centers canlead to information about clinical trials currently recruiting patients.The web site ClinicalTrials.gov also provides patients, family members, health care professionals, and members of the publiceasy access to information on clinical trials for a wide range of diseases and conditions. The National Institutes of Health(NIH), through its National Library of Medicine, has developed this site in collaboration with all NIH institutes and the FDA.The site contains information on thousands of clinical studies sponsored by the NIH, other federal agencies, and the pharma-



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ceutical industry in about 100,000 locations worldwide. Studies listed in the database are conducted primarily in the UnitedStates and Canada, but include locations in about 90 countries. ClinicalTrials.gov gives information about a trial's purpose,who may participate, locations, and phone numbers for more details. In addition, a glossary is available that will help peoplebecome familiar with the most common clinical trial terms.

Information Required for Informed ConsentThe FDA requires that people be told that the study involves research of an unproven drug, biologic(such as a vaccine, bloodproduct, or gene therapy), or medical device; the purpose of the research; how long the participant will be expected to partici-pate in the study; what will happen in the study and which parts of the study are experimental; possible risks or discomforts tothe participant; possible benefits to the participant; other procedures or treatments that might be advantageous to the partici-pant instead of the treatment being studied; that the FDA may look at study records, but the records will be kept confidential;whether any compensation and medical treatments, if any, are available if the participant is injured, what those treatments are,where they can be found, and who will pay for the treatment; the person to contact with questions about the study, partici-pants' rights, or if the participant gets hurt; that participation is voluntary and that participants can quit the study at any timewithout penalty or loss of benefits to which they are otherwise entitled.

Institutional Review BoardsClinical trial procedures are reviewed by institutional review boards (IRBs). These boards are composed of at least five mem-bers that include scientists, doctors, and lay people, and they must approve every clinical trial taking place within their juris-diction--usually a hospital. The purpose of an IRB review is to ensure that appropriate steps are taken to protect the rights andwelfare of participants as subjects of research. If the risks to participants are found to be too great, the IRB will not approvethe research, or it will specify changes that must be made before the research can be done.IRBs also review participant inclusion and exclusion requirements to be sure that appropriate people have been identified aseligible for the trial. They often look at how and where recruitment for clinical trials will occur. IRBs review the adequacy ofthe informed consent document to ensure that it includes all the elements required by law, and that it is at an appropriate read-ing level and understandable to study participants.

D. Protecting Drug QualityCDER also promotes public health by regulating the manufacture of drugs and by setting standards for drug quality. CDERworks closely with FDA field inspectors to make sure that manufacturers comply with current good manufacturing practices.Before a drug is approved, investigators determine whether the manufacturing data in the application are accurate. Once adrug is approved, another inspection is required to show the firm can consistently make a drug in large quantities. Periodicinspections check a firm's overall operation.

Current Good Manufacturing Practices (cGMPs)Current Good Manufacturing Practices (cGMPs) for human pharmaceuticals affect every American. Consumers expect thateach batch of medicines they take will meet quality standards so that they will be safe and effective. Most people, however,are not aware of cGMPs, or how FDA assures that drug manufacturing processes meet these basic objectives. FDA inspectspharmaceutical manufacturing facilities worldwide using scientifically and cGMP- trained individuals whose job it is to eval-uate whether the company is following the cGMP regulations. FDA also relies upon reports of potentially defective drugproducts from the public and the industry. FDA will often use these reports to identify sites for which an inspection or inves-tigation is needed. Most companies that are inspected are found to be fully compliant with the cGMP regulations. If a compa-ny is not complying with cGMP regulations, any drug it makes is considered adulterated under the law. This kind ofadulteration means that the drug was not manufactured under conditions that comply with cGMP. It does not mean that thereis necessarily something wrong with the drug.

For consumers currently taking medicines from a company that was not following cGMPs, FDA usually advises these con-sumers not to interrupt their drug therapy, which could have serious implications for their health. Consumers should seek ad-vice from their health care professionals before stopping or changing medications. Regulatory actions against companies withpoor cGMPs are taken as a preventive measure because the manufacturing processes do not meet FDAs regulatory standards.



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By focusing on the procedures and processes used to make these drugs, FDA is working to ensure that drugs meet their quali-ty standards and are safe and effective. The impact of cGMP violations depends on the nature of those violations and on thespecific drugs involved. A drug manufactured in violation of cGMP may still meet its labeled specifications, and the risk thatthe drug is unsafe or ineffective could be minimal. Thus, FDAs advice will be specific to the circumstances, and health careprofessionals are best able to balance risks and benefits and make the right decision for their patients.

If the failure to meet cGMPs results in the distribution of a defective drug, the company may subsequently recall that product.This protects the public by removing these drugs from the market. While FDA cannot force a company to recall a drug, com-panies will usually recall voluntarily or at FDAs request. If a company refuses to recall a drug, FDA can warn the public andcould seize the drugs that are on the market. Even if the drugs are not defective, FDA can bring a seizure or injunction case incourt to address cGMP violations. When FDA brings a seizure case, the agency asks the court for an order that allows federalofficials to take possession of adulterated drugs and destroy them. This enables FDA to immediately prevent a companyfrom distributing those drugs to consumers. When FDA brings an injunction case, FDA asks the court to order a company tostop violating cGMPs. Both seizure and injunction cases often lead to court orders that require companies to take many stepsto correct cGMP violations, such as hiring outside experts, writing new procedures, and conducting extensive training of theiremployees. FDA can also bring criminal cases because of cGMP violations, seeking fines and jail time.

E. Now Available Without a PrescriptionOver-the-counter (OTC) drug products are those drugs that are available to consumers without a prescription. There are morethan 80 classes (therapeutic categories) of OTC drugs, ranging from acne drug products to weight control drug products. Aswith prescription drugs, CDER oversees OTC drugs to ensure that they are properly labeled and that their benefits outweightheir risks.

OTC drugs play an increasingly vital role in America's health care system by providing easy access to certain drugs that canbe used safely without the help of a health care practitioner. This enables consumers to take control of their own health carein many situations. There are more than 100,000 OTC drug products marketed, encompassing about 800 significant activeingredients. The FDA has given OTC approval to drugs with such household names as Children's Advil and Children'sMotrin (ibuprofen), Orudis KT and Actron (ketoprofen), and Aleve (naproxen sodium) for pain relief and fever reduction;Femstat 3 (butoconazole nitrate) for vaginal yeast infection; Pepcid AC (famotidine), Tagamet HB (cimetidine), Zantac 75(ranitidine hydrochloride), Axid AR (nizatidine), and Prilosec OTC (omeprazole magnesium) for heartburn; Rogaine(minoxidil) for hair growth; and Claritin (loratadine), the first non-sedating antihistamine.

The FDA believes that there is an important trend toward consumer participation in their own health care. It's part of theagency's mission to keep up with the consumers' wish to be more involved. Switches have a huge impact on the health careeconomy. The greater availability of medicines over the counter saves approximately $20 billion each year, according to a1997 study. The $20 billion takes into account prescription costs, doctor visits, lost time from work, insurance costs, andtravel.

The Switch ProcessThe original Federal Food, Drug, and Cosmetic Act of 1938 made no clear-cut distinction between prescription and OTCdrugs. The 1951 Durham-Humphrey amendment to the act set up specific standards for classification. The amendment re-quires that drugs that cannot be used safely without professional supervision be dispensed only by prescription. Such drugsmay be deemed unsafe for nonprescription use because they are habit-forming or toxic, have too great a potential for harmfuleffects, or are for medical conditions that can't be readily self-diagnosed. All other drugs can be sold OTC. A drug must bemade available without a prescription if, by following the labeling, consumers can use it safely and effectively without pro-fessional guidance.The process of reclassifying drugs from prescription to OTC status is referred to as an "Rx to OTC switch." Drugs are com-monly switched one of two ways: under the "OTC drug review," or by a manufacturer's submission of additional informationto the original new drug application. The OTC drug review, which began in 1972, is an ongoing assessment of the safety andeffectiveness of all nonprescription drugs. In the first phase of the OTC drug review, panels of nongovernment experts review



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active ingredients in marketed OTC drug products to determine whether they can be classified as safe and effective. The pan-els also review prescription ingredients to determine whether some are appropriate for OTC marketing.

The second common path to OTC approval is under the new drug application process. Under this process, manufacturers sub-mit data to the FDA showing the drug is appropriate for self-administration. Data are submitted in a new drug application or asupplement to an already approved drug application. Often the submission includes studies showing that the product's label-ing can be read, understood, and followed by the consumer without the guidance of a health care provider. The FDA reviewsthe new data, along with any information known about the drug from its prescription use. Under the new drug applicationprocess, some drugs are approved initially as OTC drugs, but most are first approved for prescription use and later switchedto OTC.

In almost every case for the first drug switched in a drug category, the agency has sought the recommendation of a joint advi-sory committee made up of members of the agency's Nonprescription Drugs Advisory Committee and another advisory com-mittee with expertise in the type of drug being considered. For example, because Rogaine is for conditions of the hair andscalp, representatives of the Dermatologic and Ophthalmic Drugs Advisory Committee participated. While not bound by theadvisory committee's counsel, the FDA almost always follows its recommendation.

Benefit-Risk ComparisonWhen considering an Rx-to-OTC switch, the key question for the FDA is whether patients alone can achieve the desired med-ical result without endangering their safety. No drug is absolutely safe. There are risks associated with every medication, sothe FDA does a benefit-to-risk comparison to determine whether it is appropriate for consumers to self-medicate with a drugfor a certain use. On the safety side, the agency looks at the drug's toxicity--its potential for poisonous effects--when the drugis used according to its labeled directions, and also from foreseeable misuse of the drug.

The FDA weighs a drug's safety against its benefit to patients. The agency considers whether consumers will be able to un-derstand and follow label directions, whether patients can diagnose the condition themselves--or at least recognize the symp-toms they want to treat--and whether routine medical examinations or laboratory tests are required for continued safe use of adrug. No easy risk-benefit formula exists. The FDA does a case-by-case review of each drug because each drug raises uniqueissues. Concerns about side effects can sometimes be managed by approving OTC drugs at lower doses than their prescrip-tion counterparts. The drugs must still be effective for the short-term symptoms for which they're intended. The issue ofwhether a condition can be self-diagnosed was a central one for the advisory committee reviewing Rogaine. Most OTC drugsare intended for treatment of symptoms that can be easily recognized, like headache or upset stomach. Others, though, areintended to treat diseases like asthma or vaginal fungal infections, which cannot be consumer-diagnosed.

Consumer-Friendly LabelingLabeling is an influential element in the OTC risk-benefit comparison. The decision about a drug's safety for OTC use can'tbe made in a vacuum, by looking only at the drug ingredients. Every drug, used improperly, can cause adverse reactions.Even appropriate use can lead to side effects (antihistamine use may cause drowsiness, for example). And some drugs can bedangerously unsafe or ineffective if taken while using certain other drugs. Labeling can alert consumers to such potentialproblems. Labeling of all drugs must be clear and truthful. For OTC drugs, the intended uses, directions, and warnings haveto be written so consumers, including individuals with low reading comprehension, can understand them.

In March 1999, the FDA finalized regulations to increase the readability of OTC labels by making the language more con-sumer-friendly and standardizing the format, including where important information is placed. The FDA believes that, insome cases, consumers can get more information in the OTC labeling than they would get from their doctors. An example ofthe consumer-friendly OTC label, available from the FDA website, is shown below.



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A Popular AlternativeUnder the law, OTC drugs may be advertised directly to consumers without the many restrictions placed on prescriptionproducts. OTC status provides a greater opportunity for direct communication with the consumer, not only by advertising inmagazines and on television, but also with packaging, brochures, and retail displays. Today's emphasis on self-care fuels thepopularity of nonprescription drugs. But OTC products are intended to supplement the medical options of the consumer, notsubstitute for a prescriber's medical knowledge. If a health problem persists or worsens while using an OTC drug, consult ahealth care provider. People must be in a partnership with their health care providers for optimal health. Many situationsaren't appropriate for self-treatment, and others may require professional guidance for self-treatment.

F. Postmarketing Surveillance ProgramsDespite CDER's vigilant premarket review, active postmarketing surveillance of drug adverse effects is also essential. Be-cause all possible side effects of a drug can't be anticipated based on preapproval studies involving only several hundred toseveral thousand patients, FDA maintains a system of postmarketing surveillance and risk assessment programs to identifyadverse events that did not appear during the drug approval process. FDA monitors adverse events such as adverse reactionsand poisonings. The Agency uses this information to update drug labeling, and, on rare occasions, to reevaluate the approvalor marketing decision.

The following describes how CDER works to assure the ongoing safety and effectiveness of drug products currently market-ed in the United States.

The Adverse Event Reporting System (AERS) is a computerized information database designed to support the FDA's post-marketing safety surveillance program for all approved drug and therapeutic biologic products. The ultimate goal of AERS isto improve the public health by providing the best available tools for storing and analyzing safety reports. The reports in



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AERS are evaluated by a multidisciplinary staff safety evaluators, epidemiologists and other scientists in CDERs Office ofSurveillance and Epidemiology to detect safety signals and to monitor drug safety. As a result, the FDA may take regulatoryactions to improve product safety and protect the public health, such as updating a product's labeling information, sending outa "Dear Health Care Professional" letter, or re-evaluating an approval decision.

The MedWatch program is for health professionals and the public to voluntarily report serious reactions and problems withmedical products, such as drugs and medical devices. It also ensures that new safety information is rapidly communicated tothe medical community thereby improving patient care. All data contained on the MedWatch form will be entered into theAERS database. After the FDA evaluates reports, the result may be safety alerts, letters to health care professionals, labelingchanges, product withdrawals, or further postmarketing research. When the FDA receives a MedWatch report, it is enteredinto a database that allows a safety evaluator to compare it to similar reports. As few as a handful of reports may trigger acareful investigation by the FDA and a manufacturer. To report to MedWatch, log onto the MedWatch site atwww.fda.gov/medwatch/. Reports can be made online, by phone (1-800-FDA-1088), or by downloading a form to fax (1-800-FDA-0178) or mail (MedWatch, FDA,5600 Fishers Lane, Rockville, MD 20852-9787).

Manufacturers of prescription medical products are required by regulation to submit adverse event reports to the FDA. TheMedWatch site provides information on mandatory reporting by manufacturers. In addition, drug manufacturers must submiteither error and accident reports or drug quality reports when deviation from current good manufacturing practice regulationsoccur.

G. Strategies to Reduce Medication Errors: Working to Improve Medication SafetyFDA receives medication error reports on marketed human drugs (including prescription drugs, generic drugs, and over-the-counter drugs) and nonvaccine biological products and devices. The National Coordinating Council for Medication Error Re-porting and Prevention defines a medication error as "any preventable event that may cause or lead to inappropriate medica-tion use or patient harm while the medication is in the control of the health care professional, patient, or consumer. Suchevents may be related to professional practice, health care products, procedures, and systems, including prescribing; ordercommunication; product labeling, packaging, and nomenclature; compounding; dispensing; distribution; administration; edu-cation; monitoring; and use." CDER medication errors program staff review medication error reports sent to the Institute ofSafe Medication Practices (ISMP) and MedWatch, evaluate causality, and analyze the data to provide feedback to others atFDA.

A Regulatory ApproachThe public took notice in 1999 when the Institute of Medicine (IOM) released a report, "To Err is Human: Building a SaferHealth System." According to the report, between 44,000 and 98,000 deaths may result each year from medical errors in hos-pitals alone, with more than 7,000 deaths each year related to medications. In response to the IOM's report, all parts of theU.S. health system put error reduction strategies into high gear by re-evaluating and strengthening checks and balances toprevent errors.

The FDA enhanced its efforts to reduce medication errors by dedicating more resources to drug safety, which included form-ing a new division on medication errors at the agency in 2002. Some important ways the FDA has worked to reduce medica-tion errors includes: issuing a bar code label rule; reviewing drug names to minimize confusion between look or sound alikedrug names; improving OTC and prescription labels; publishing information for consumers and health professionals regard-ing new drug warnings and other safety information; and launching several medication risk reduction projects.

H. Direct-to-Consumer AdvertisingWhen it comes to advertising prescription drugs on radio and television and in magazines, doctors say that, for the most part,the ads have both positive and negative effects on their patients and practices. Results of a FDA survey, released in 2004, alsoindicate that most physicians view direct-to-consumer (DTC) ads as one of many factors that affect their medical practicesand their interactions with patients.



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For decades, prescription drug makers promoted their products exclusively to health care professionals, who were expected tointerpret drug information for their patients. Beginning in the early 1990s, some drug manufacturers began targeting consum-ers due, in part, to the aging baby boomers and to an increase in the number of patients participating in their own health caredecisions. Since then, DTC advertising has become a popular promotional tool.

The FDA oversees the advertising of prescription drug products under the Federal Food, Drug, and Cosmetic Act and relatedregulations. The FDAs Division of Drug Marketing, Advertising, and Communications (DDMAC) helps protect the publichealth by assuring prescription drug information is truthful, balanced and accurately communicated. This is accomplishedthrough a comprehensive surveillance, enforcement and education program, and by fostering better communication of label-ing and promotional information to both healthcare professionals and consumers.

DDMAC reviewers have responsibility for reviewing prescription drug advertising and promotional labeling to ensure thatthe information contained in these promotional materials is not false or misleading. They engage in a variety of tasks to per-form this responsibility, including: providing written comments to pharmaceutical sponsors on proposed promotional materi-als to ensure clear and unambiguous communication of the laws and regulations relating to prescription drug promotion;reviewing complaints about alleged promotional violations; initiating enforcement actions on promotional materials that arefalse or misleading; comparing the product labeling and promotional materials of various closely related products to ensurethat the regulatory requirements are consistently and equitably applied; traveling to major medical meetings and pharmaceuti-cal conventions to monitor promotional exhibits and activities; and acting as a liaison between DDMAC and other divisionswithin the FDA on promotional issues.

DDMAC also reminds all companies who are engaging in DTC advertising of prescription drugs that the requirements of sec-tion 906 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) went into effect on March 25, 2008. Sec-tion 906 of FDAAA mandates that published direct-to-consumer advertisements for prescription drugs include the followingstatement printed in conspicuous text: "You are encouraged to report negative side effects of prescription drugs to the FDA.Visit www.fda.gov/medwatch, or call 1-800-FDA-1088."



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Chapter 2: Federal Drug Control Law

I. The Federal Food, Drug & Cosmetic Act (FDCA) Passed by the United States Congress in 1938, and amended many times since then, the FDCA serves as the basis fordrug regulation in the United States. The FDCA is both simple and complex at the same time. The simplicity is that it speci-fies only three basic illegal acts; adulteration, misbranding, and the placing into interstate commerce of an unapproved newdrug. The complexity is that many activities are included under the umbrella of these three basic illegal acts. If you are everchallenged to explain why something you know to be illegal is illegal under the FDCA, a safe explanation would be to assertthat the activity is either adulteration, misbranding, or the placing into interstate commerce of an unapproved new drug.

The passage of the FDCA in 1938 had a catalyst: the sulfanilamide tragedy of 1937. This miracle anti-infective sulfadrug was made into an elixir that contained diethylene glycol. With no toxicity tests completed, the elixir led to 107 deaths,mostly children. Unfortunately, the Pure Food and Drug Act (which was passed in 1906 and active in 1937) did not allow theFDA to ban unsafe drugs. Since 1938, there have been a number of amendments to the FDCA that are important to be famil-iar with. These include:

Durham-Humphrey Amendment of 1951. This amendment distinguished at the federal level those drugs requiring a prescrip-tion from nonprescription drugs. Prescription drugs were defined as drugs that could not be used safely without medicalsupervision, and restricted the sale of such drugs to prescription by a licensed practitioner. In addition to requiring a pre-scription for specific drugs, the Durham Humphrey Amendment also provided statutory provisions for the receipt of oralprescriptions as well as allowing for the refilling of prescriptions. Prescription drugs required the legend Caution: Fed-eral law prohibits dispensing without a prescription.

Kefauver-Harris Amendment of 1962. This amendment, also known as the Drug Efficacy Amendment, was enacted due tothe worldwide Thalidomide disaster, and required drugs (RX and OTC) to be proven safe AND effective by the FDA.The efficacy requirement was retroactive to 1938 (DESI Project).

Orphan Drug Act of 1983. This amendment provided for tax and exclusive licensing incentives for manufactures to developand market drugs that were too expensive to develop and market for diseases that affect fewer than 200,000 Americans.

Drug Price Competition and Patent-Term Restoration Act of 1984. Also known as the Waxman-Hatch Amendment, itstreamlined the generic drug approval process and made generic drugs more readily available to the public, while provid-ing incentives for manufacturers to develop new drugs through possible extension of patent life.

Prescription Drug Marketing Act of 1987. This amendment, enacted in response to threats of public health by secondary dis-tribution systems, restricted sales and established record keeping requirements for prescription samples. It also prohibit-ed health care entities from reselling their purchases to other businesses, and required state licensing of drug wholesalers.

Dietary Supplement Health and Education Act (DSHEA) of 1994. This amendment permitted manufacturers to make certainclaims not allowed under the FDCA for dietary supplements. Under DSHEA, the FDA was to treat dietary supplementsmore like foods than drugs.

Food and Drug Administration Modernization Act of 1997. This amendment streamlined the regulatory procedures to ensurethe expedited availability of safe and effective drugs and devices. In addition, it increased the FDAs public accountabili-ty, allowed for a fast tract approval process for drugs to treat serious/life threatening diseases, and established a databankof information on clinical trials.

A. DefinitionsImportant to a thorough understanding of the FDCA is a knowledge of how the FDCA defines the terms to which it frequent-ly refers. Whether an activity falls outside or inside a definition under the act may well determine whether the activity is law-



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ful or unlawful. Some of the most important definitions follow. The language is quoted directly from the FDCA.Numerations refer to subsections of Section 321, Title 21, of the United States Code.

(g) (1) The term "drug" means (A) articles recognized in the official United States Pharmacopoeia, official Homoeo-pathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or otheranimals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or oth-er animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C). A foodor dietary supplement for which a claim is made... is not a drug solely because the label or the labeling contains sucha claim. A food, dietary ingredient, or dietary supplement for which a truthful and not misleading statement ismade... is not a drug under clause (C) solely because the label or the labeling contains such a statement.

Note that the definition of drug is dependent on the intended use of the article, not on the actual use of it. And the relevantintent is that of the provider of the article, not the user of the article. A single article may be a drug in one context, and not bea drug in another context, because the intent of the provider changes between the two contexts. Note also that subsections(B) and (C) differ significantly, because in (B) an article can be a drug due to its intended use in therapeutics, while in (C) anarticle can be a drug merely due to its intended use in affecting the structure or function of the body.

(h) The term "device" . . . means an instrument, apparatus, implement, machine, contrivance, implant, in vitro re-agent, or other similar or related article, including any component, part, or accessory, which is-- (1) recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, (2) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or preven-tion of disease, in man or other animals, or (3) intended to affect the structure or any function of the body of man or other animals, and which does not achieveits primary intended purposes through chemical action within or on the body of man or other animals and which isnot dependent upon being metabolized for the achievement of its primary intended purposes.

Note that the principle distinction between drugs and devices is that drugs achieve their intended purpose through chemicalaction while devices do not. Sometimes the distinction between drugs and devices is blurry, and it is important to ask in whatway the article achieves its intended purpose. The terms drug and device are mutually exclusive. A single article cannotbe both.

(i) The term "cosmetic" means (1) articles 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, oraltering the appearance, and (2) articles intended for use as a component of any such articles; except that such termshall not include soap.

The FDCA definition of cosmetic is relatively consistent with the lay usage of that term. The terms cosmetic and drugare not mutually exclusive. A single article can be both.

(j) The term "official compendium" means the official United States Pharmacopoeia, official Homoeopathic Pharma-copoeia of the United States, official National Formulary, or any supplement to any of them.

Official Compendia set standards with which those who are responsible for drug formulation and distribution must comply.Many of the requirements for drugs are not explicitly stated within the FDCA because the act defers to an official compendi-um and merely requires compliance with compendial standards. This does not mean that there are no legally mandated stan-dards; only that the standards are contained within a compendium that is adopted by reference within the act.

(k) The term "label" means a display of written, printed, or graphic matter upon the immediate container of any arti-cle.



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(m) The term "labeling" means all labels and other written, printed, or graphic matters (1) upon any article or any ofits containers or wrappers, or (2) accompanying such article.

Note that labeling includes the label. It is to the labeling that attention usually turns when decisions are made about theintent of a provider of an article. It is the labeling that will frequently make the difference between an act being legal or ille-gal. Because the FDCA is oriented toward the product, rather than the prescibers and dispensers of the product, the labelingis considered part of the product.

(p) The term "new drug" means-- (1) Any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composi-tion of which is such that such drug is not generally recognized, among experts qualified by scientific training andexperience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the condition pre-scribed, recommended, or suggested in the labeling thereof, except that such a drug not so recognized shall not bedeemed to be a "new drug" if at any time prior to the enactment of this Act [enacted June 25, 1938] it was subject tothe Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same represen-tations concerning the conditions of its use; or (2) Any drug (except a new animal drug or an animal feed bearing orcontaining a new animal drug) the composition of which is such that such drug, as a result of investigations to deter-mine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, other-wise than in such investigations, been used to a material extent or for a material time under such conditions.

Note that whether a drug is new or not new (most people who are familiar with pharmacy law use the phrase not newdrug rather than old drug), depends on its general recognition as safe and effective under the conditions suggested in thelabeling. As the labeling changes, perceptions of newness may change. Only new drugs must be shown to be safe and effec-tive prior to their being placed into interstate commerce. Not new drugs must meet all other relevant requirements fordrugs (i.e., adulteration and misbranding provisions), but not those applicable to new drugs, because they are not new.

B. AdulterationA drug may be adulterated either because it is actually adulterated or because it is deemed to be adulterated due to some re-quirement for proper storage or handling not having been met. The FDCA adopts a take-no-chances approach. It also recog-nizes the practical difficulties of proving that an article actually is adulterated. Thus, the act creates circumstances underwhich the assumption is made that an article must be adulterated. These assumptions are virtually impossible to rebut. Se-lected language of the act follows. Numerations refer to subsections of Section 351, Title 21, of the United States Code.

A drug or device shall be deemed to be adulterated--(a)(1) If it consists in whole or in part of any filthy, putrid, or decomposed substance; or (2)(A) if it has been pre-pared, packed, or held under insanitary conditions whereby it may have been contaminated with filth, or whereby itmay have been rendered injurious to health; or (B) if it is a drug and the methods used in, or the facilities or controlsused for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered inconformity with current good manufacturing practice to assure that such drug meets the requirements of this Act asto safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or isrepresented to possess; . . .

(b) If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and itsstrength differs from, or its quality or purity falls below, the standard set forth in such compendium. . .(c) If it is not subject to the provisions of paragraph (b) of this section and its strength differs from, or its purity orquality falls below, that which it purports or is represented to possess.(d) If it is a drug and any substance has been (1) mixed or packed therewith so as to reduce its quality or strength or(2) substituted wholly or in part therefor.

Note that a drug may be adulterated either because it is actually adulterated in some way (contamination by a foreign sub-stance, for example), or because it has been deemed to be adulterated due to the possibility of its being adulterated (by beingheld under unsanitary conditions, for example).



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C. MisbrandingThe FDCA requires that any information a manufacturer places on the label of a drug be truthful and not misleading. In addi-tion, the act imposes certain mandatory disclosure requirements. So a provider of drugs cannot get cute and omit informationthat is mandated, else the provider will violate the disclosure requirement. And the provider cannot disclose in a misleadingway or the provider will violate the basic requirement of truth. This is essentially a Catch 22" situation, in which the onlyway out is full and truthful (not misleading) disclosure. Selected language of the act follows. Numerations refer to subsec-tions of Section 352, Title 21, of the United States Code.

A drug or device shall be deemed to be misbranded--(a) If its labeling is false or misleading in any particular...(b) If in package form unless it bears a label containing (1) the name and place of business of the manufacturer,packer, or distributor; and (2) an accurate statement of the quantity of the contents in terms of weight, measure, ornumerical count: Provided, That under clause (2) of this paragraph reasonable variations shall be permitted, andexemptions as to small packages shall be established, by regulations prescribed by the Secretary.(c) If any word, statement, or other information required by or under authority of this Act to appear on the label orlabeling is not prominently placed thereon with such conspicuousness (as compared with other words, statements,designs, or devices, in the labeling) and in such terms as to render it likely to be read and understood by the ordinaryindividual under customary conditions of purchase and use.(e)(1)(A) If it is a drug, unless its label bears... (i) the established name... of the drug, if there is such a name; ii) theestablished name and quantity or... the proportion of each active ingredient, including the quantity, kind, and pro-portion of any alcohol,... (iii) the established name of each inactive ingredient listed in alphabetical order on the out-side container of the retail package and, if determined to be appropriate... on the immediate container... except thatnothing in this subclause shall be deemed to require that any trade secret be divulged, and except that the require-ments of this subclause with respect to alphabetical order shall apply only to nonprescription drugs that are not alsocosmetics and that this subclause shall not apply to nonprescription drugs not intended for human use. (B) For anyprescription drug the established name of such drug or ingredient, as the case may be, on such label (and on any la-beling on which a name for such drug or ingredient is used) shall be printed prominently and in type at least half aslarge as that used thereon for any proprietary name or designation for such drug or ingredient, except that to the ex-tent that compliance with the requirements of subclause (ii) or (iii) of clause (A) or this clause is impracticable, ex-emptions shall be established by regulations promulgated by the Secretary. (2) If it is a device and it has anestablished name, unless its label bears, to the exclusion of any other nonproprietary name, its established name...prominently printed in type at least half as large as that used thereon for any proprietary name or designation forsuch device, except that to the extent compliance with the requirements of this subparagraph is impracticable, ex-emptions shall be established by regulations promulgated by the Secretary. (3) As used in subparagraph (1), theterm "established name," with respect to a drug or ingredient thereof, means (A) the applicable official name desig-nated... or (B) if there is no such name and such drug, or such ingredient, is an article recognized in an official com-pendium, then the official title thereof in such compendium, or (C) if neither clause (A) nor clause (B) of thissubparagraph applies, then the common or usual name...(f) Unless its labeling bears (1) adequate directions for use; and (2) such adequate warnings against use in thosepathological conditions or by children where its use may be dangerous to health, or against unsafe dosage or meth-ods or duration of administration or application, in such manner and form, as are necessary for the protection of us-ers, except that where any requirement of clause (1) of this paragraph, as applied to any drug or device, is notnecessary for the protection of the public health, the Secretary shall promulgate regulations exempting suchdrug/device from such requirement.(g) If it purports to be a drug the name of which is recognized in an official compendium, unless it is packaged andlabeled as prescribed therein. . . .(h) If it has been found ... to be a drug liable to deterioration, unless it is packaged in such form and manner, and itslabel bears a statement of such precautions, ...as necessary for the protection of the public health. . . .(i) If it is a drug and its container is so made, formed, or filled as to be misleading, or (2) if it is an imitation of an-other drug; or (3) if it is offered for sale under the name of another drug.



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(j) If it is dangerous to health when used in the dosage, or manner or with the frequency or duration prescribed, rec-ommended, or suggested in the labeling thereof.(m) If it is a color additive the intended use of which is for the purpose of coloring only, unless its packaging and la-beling are in conformity with such packaging and labeling requirements applicable to such color additive...(n) In the case of any prescription drug distributed or offered for sale in any State, unless the manufacturer, packer,or distributor thereof includes in all advertisements and other descriptive printed matter issued ... a true statement of(1) the established name... printed prominently and in type at least half as large as that used for any trade or brandname thereof, (2) the formula showing quantitatively each ingredient of such drug... and (3) such other informationin brief summary relating to side effects, contraindications, and effectiveness as shall be required in regulationswhich shall be issued by the Secretary...(p) If it is a drug and its packaging or labeling is in violation of an applicable regulation issued pursuant to section 3or 4 of the Poison Prevention Packaging Act of 1970 [15 USCS 1472 or 1473].

Note that the general purpose of the misbranding provisions is to assure that accurate and complete information accompaniesevery drug product, which applies to advertisements as well as to other product-related materials. Furthermore, a drug will beconsidered misbranded if it does not comply with the Poison Prevention Packaging Act.

D. New Drug ApprovalOne of the most controversial aspects of the FDCA is the restrictive provision regarding the approval of new drugs. TheFood and Drug Administration (FDA) is criticized by some because it is too lenient in its interpretation of the FDCA and per-mits new drugs to be marketed without adequate studies for safety and efficacy, while others criticize the agency for beingtoo strict and preventing the use of perfectly safe and effective remedies that are needed by people who are ill and near death.In response to these criticisms, the agency has attempted to speed up approval of those new drugs that represent a significantadvance in therapy, while continuing to maintain a healthy skepticism regarding new drugs that are not as likely to advancetherapy and have the potential to cause significant harm. The language of the act follows. Numerations refer to subsectionsof Section 355, Title 21, of the United States Code.

(a) No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approvalof an application filed pursuant to subsection (b) or (j) is effective with respect to such drug.(b) (1) Any person may file with the Secretary an application with respect to any drug subject to the provisions ofsubsection (a). Such person shall submit to the Secretary as a part of the application (A) full reports of investigationswhich have been made to show whether or not such drug is safe for use and whether such drug is effective in use; (B)a full list of the articles used as components of such drug; (C) a full statement of the composition of such drug; (D) afull description of the methods used in, and the facilities and controls used for, the manufacture, processing, andpacking of such drug; (E) such samples of such drug and of the articles used as components thereof as the Secretarymay require; and (F) specimens of the labeling proposed to be used for such drug.

The information that must be included in an NDA is quite specific, and the brief list cited above is misleading in its simplici-ty. In fact, an NDA includes massive amounts of information beyond what is described here, because often FDA reviewersrequire additional information to maintain a comfort zone regarding product safety and efficacy. In addition to safety andefficacy information, product sponsors must include information about the patent status of the product they sponsor.

E. Prescription ExemptionSome medications are so potentially hazardous to health that the law recognizes they are not capable of being labeled for safeand effective use without medical supervision. For these drugs, a prescription is required before a pharmacist may dispensethem to a patient. These drugs must bear the federal legend on the label affixed to each stock bottle provided to pharma-cists. When dispensed to patients, these drugs must be labeled with specific information required by the FDCA, but undersuch circumstances the drug is exempt from most requirements of the misbranding provisions. Other drugs are of such acharacter that they can be labeled for safe and effective use without medical supervision, thus they are available without a



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prescription. The FDCA specifies the conditions and characteristics that will cause a drug to be classified as Rx or OTC.The language of the act follows. Numerations refer to subsections of Section 353, Title 21, of the United States Code.

(b)(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 the collateral mea-sures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to admin-ister such drug; or (B) is limited by an approved application under section 505 [21 USCS 355] to use under the professional su-pervision of a practitioner licensed by law to administer such drug, shall be dispensed only (i) upon a written pre-scription of a practitioner licensed by law to administer such drug, or (ii) upon an oral prescription of suchpractitioner which is reduced promptly to writing and filed by the pharmacist, or (iii) by refilling any such written ororal prescription if such refilling is authorized by the prescriber either in the original prescription or by oral orderwhich is reduced promptly to writing and filed by the pharmacist. The act of dispensing a drug contrary to the provi-sions of this paragraph shall be deemed to be an act which results in the drug being misbranded while held for sale.

Note the two ways for a product to be classified as prescription-only: (1) lack of safety if used without medical supervision,and (2) the sponsors request for prescription-only classification in the products NDA. Note also the three ways in which aprescription may be authorized by a prescriber; (1) in writing, (2) verbal authorization, and (3) refilling a written or verbalorder. Finally, the dispensing of a prescription drug without a prescription is a misbranding violation, because the law saysso; regardless of the truthfulness and non-misleading nature of the drug labeling.

(2) Any drug dispensed by filling or refilling a written or oral prescription of a practitioner licensed by law to ad-minister such drug shall be exempt from the requirements of section 502 [21 USCS 352], except paragraphs (a),(i)(2) and (3), (k), and (l) [21 USCS 352(a), (i)(2), (3), (k), (l)], and the packaging requirements of paragraphs (g),(h) and (p) [21 USCS 352(g), (h), (p)], if the drug bears a label containing the name and address of the dispens-er, the serial number and date of the prescription or of its filling, the name of the prescriber, and, if stated in theprescription, the name of the patient, and the directions for use and cautionary statements, if any, contained insuch prescription. This exemption shall not apply to any drug dispensed in the course of the conduct of a business ofdispensing drugs pursuant to diagnosis by mail, or to a drug dispensed in violation of paragraph (1) of this subsec-tion.

Note the information that is required to appear on the label of a drug prescribed for a patient, when the drug is dispensed tothe patient. Some pieces of information are mandatory for every prescription, other pieces of information need be includedon the label only when they are contained in the prescription. The very important effect of this section is to exempt frommost important misbranding provisions those drugs that are dispensed pursuant to a prescription and are properly labeled.This is the reason why requirements such as the adequate directions for use requirement need not be met by pharmacistsdispensing properly labeled drugs pursuant to a prescription; the drug is exempt from that requirement.

(3) The Secretary may by regulation remove drugs subject to section 505 [21 USCS 355] from the requirementsof paragraph (1) of this subsection when such requirements are not necessary for the protection of the public health. (4) (A) A drug that is subject to paragraph (1) shall be deemed to be misbranded if at any time prior to dispensingthe label of the drug fails to bear, at a minimum, the symbol "Rx only". (B) A drug to which paragraph (1) does not apply shall be deemed to be misbranded if at any time prior to dis-pensing the label of the drug bears the symbol described in subparagraph (A).

Note that drugs may be switched from prescription to non-prescription status. They must contain the federal legend, which isnow Rx Only, but used to be Caution: Federal law prohibits dispensing without a prescription. If the label of a non-pre-scription drug contains this federal legend, then the drug is misbranded.

F. Prohibited ActsIt would be nice to think that all parties involved in drug development, marketing, and distribution could be trusted to volun-tarily comply with requirements of the FDCA, and that there would be no need to actually enforce the law through penalties.



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Actually, voluntary compliance with the act is quite prevalent, but occasionally there are those who test the waters by goingout on a limb and conducting themselves in ways that the law simply cannot allow. Very rarely there are others who simplyhave no respect for the law or for the public health, and they conduct themselves in ways that cannot be tolerated. In eitherevent, the FDCA contains within it provisions to penalize those who fail to voluntarily comply with the law. These penaltiesvary in severity, and can be used as necessary to protect the public health. The language of the act follows. Numerations re-fer to subsections of Section 331, Title 21, of the United States Code.

The following acts and the causing thereof are hereby prohibited:(a) The intro

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