How FDA Approves Drugs and Regulates
Their Safety and Effectiveness
Susan Thaul
Specialist in Drug Safety and Effectiveness
June 25, 2012
Congressional Research Service
7-5700
www.crs.gov
R41983
CRS Report for Congress
Pr
epared for Members and Committees of Congress
How FDA Approves Drugs and Regulates Their Safety and Effectiveness
Summary
Update: On June 20, 2012, the House of Representatives passed, by voice vote and under
suspension of the rules, S. 3187 (EAH), the Food and Drug Administration Safety and Innovation
Act, as amended. This bill would reauthorize the FDA prescription drug and medical device user
fee programs (which would otherwise expire on September 30, 2012), create new user fee
programs for generic and biosimilar drug approvals, and make other revisions to other FDA drug
and device approval processes. It reflects bicameral compromise on earlier versions of the bill (S.
3187 [ES], which passed the Senate on May 24, 2012, and H.R. 5651 [EH], which passed the
House on May 30, 2012). The following CRS reports provide overview information on FDA’s
processes for approval and regulation of drugs:
• CRS Report R41983, How FDA Approves Drugs and Regulates Their Safety and
Effectiveness, by Susan Thaul.
• CRS Report RL33986, FDA’s Authority to Ensure That Drugs Prescribed to
Children Are Safe and Effective, by Susan Thaul.
• CRS Report R42130, FDA Regulation of Medical Devices, by Judith A. Johnson.
• CRS Report R42508, The FDA Medical Device User Fee Program, by Judith A.
Johnson.
(Note: The rest of this report has not been updated since September 1, 2011.)
The Food and Drug Administration (FDA) is a regulatory agency within the Department of
Health and Human Services. A key responsibility is to regulate the safety and effectiveness of
drugs sold in the United States. FDA divides that responsibility into two phases: preapproval
(premarket) and postapproval (postmarket). FDA reviews manufacturers’ applications to market
drugs in the United States; a drug may not be sold unless it has FDA approval. The agency
continues its oversight of drug safety and effectiveness as long as the drug is on the market.
Beginning with the Food and Drugs Act of 1906, Congress has incrementally refined and
expanded FDA’s responsibilities regarding drug approval and regulation.
The progression to drug approval begins before FDA involvement. First, basic scientists work in
the laboratory and with animals; second, a drug or biotechnology company develops a prototype
drug. That company must seek and receive FDA approval, by way of an investigational new drug
(IND) application, to test the product with human subjects. Those tests, called clinical trials, are
carried out sequentially in Phase I, II, and III studies, which involve increasing numbers of
subjects. The manufacturer then compiles the resulting data and analysis in a new drug
application (NDA). FDA reviews the NDA with three major concerns: (1) safety and
effectiveness in the drug’s proposed use; (2) appropriateness of the proposed labeling; and
(3) adequacy of manufacturing methods to assure the drug’s identify, strength, quality, and
identity. The Federal Food, Drug, and Cosmetic Act (FFDCA) and associated regulations detail
the requirements at each step. FDA uses a few special mechanisms to expedite drug development
and the review process when a drug might address an unmet need or a serious disease or
condition. Those mechanisms include accelerated approval, animal efficacy approval, fast track
applications, and priority review.
Once a drug is on the U.S. market (following FDA approval of the NDA), FDA continues to
address drug production, distribution, and use. Its activities, based on ensuring drug safety and
Congressional Research Service
How FDA Approves Drugs and Regulates Their Safety and Effectiveness
effectiveness, address product integrity, labeling, reporting of research and adverse events,
surveillance, drug studies, risk management, information dissemination, off-label use, and direct-
to-consumer advertising, all topics in which Congress has traditionally been interested.
FDA seeks to ensure product integrity through product and facility registration; inspections;
chain-of-custody documentation; and technologies to protect against counterfeit, diverted,
subpotent, adulterated, misbranded, and expired drugs. FDA’s approval of an NDA includes the
drug’s labeling; the agency may require changes once a drug is on the market based on new
information. It also prohibits manufacturer promotion of uses that are not specified in the
labeling. The FFDCA requires that manufacturers report to FDA adverse events related to its
drugs; clinicians and other members of the public may report adverse events to FDA. The
agency’s surveillance of drug-related problems, which had primarily focused on analyses of
various adverse-event databases, is now expanding to more active uses of evolving computer
technology and linking to other public and private information sources.
The FFDCA allows FDA to require a manufacturer to conduct postapproval studies of drugs. The
law specifies when FDA must attach the requirement to the NDA approval and when FDA may
issue the requirement after a drug is on the market. To manage exception risks of drugs, FDA may
require patient or clinician guides and restrictions on distribution. The agency publicly
disseminates information about drug safety and effectiveness; and regulates the industry
promotion of products to clinicians and the public.
Congressional Research Service
How FDA Approves Drugs and Regulates Their Safety and Effectiveness
Contents
Legislative History of Drug Regulation........................................................................................... 1
How FDA Approves New Drugs ..................................................................................................... 2
The Standard Process of Drug Approval ................................................................................... 3
Investigational New Drug (IND) Application..................................................................... 4
Clinical Trials ...................................................................................................................... 4
New Drug Application (NDA) ............................................................................................ 4
FDA Review........................................................................................................................ 5
Special Mechanisms to Expedite the Development and Review Process ................................. 6
How FDA Regulates Approved Drugs............................................................................................. 8
FDA Offices Responsible for Drug Postapproval Regulation................................................... 8
FDA Drug-Regulation Activities............................................................................................... 9
Product Integrity................................................................................................................ 10
Labeling............................................................................................................................. 11
Reporting........................................................................................................................... 12
Surveillance....................................................................................................................... 12
Drug Studies...................................................................................................................... 13
Risk Management.............................................................................................................. 14
Information Dissemination................................................................................................ 17
Off-Label Use.................................................................................................................... 18
Direct-to-Consumer Advertising ....................................................................................... 19
Figures
Figure 1. Drug Development Path ................................................................................................... 3
Tables
Textbox 1. Examples of Drug Laws that Amended the FFDCA ..................................................... 2
Textbox 2. Safety, Efficacy, and Effectiveness ................................................................................ 4
Textbox 3. Accelerated Approval, Fast Track, and Priority Review................................................ 7
Textbox 4. Example: Same Data, Different Decisions .................................................................. 11
Textbox 5. Balancing Risks and Benefits ...................................................................................... 15
Textbox 6. Examples of Off-Label Use ......................................................................................... 18
Contacts
Author Contact Information........................................................................................................... 19
Congressional Research Service
How FDA Approves Drugs and Regulates Their Safety and Effectiveness
he Food and Drug Administration (FDA) oversees the approval and regulation of drugs
entering the U.S. market. Two regulatory frameworks support the FDA’s review of
T prescription drugs. First, FDA reviews the safety and effectiveness of new drugs that
manufacturers wish to market in the United States; this process is called premarket approval or
preapproval review. Second, once a drug has passed that threshold and is FDA-approved, FDA
acts through its postmarket or post-approval regulatory procedures.
Update: On June 20, 2012, the House of Representatives passed, by voice vote and under suspension of the rules, S.
3187 (EAH), the Food and Drug Administration Safety and Innovation Act, as amended. This bill would reauthorize
the FDA prescription drug and medical device user fee programs (which would otherwise expire on September 30,
2012), create new user fee programs for generic and biosimilar drug approvals, and make other revisions to other
FDA drug and device approval processes. It reflects bicameral compromise on earlier versions of the bill (S. 3187
[ES], which passed the Senate on May 24, 2012, and HR 5651 [EH], which passed the House on May 30, 2012). The
fol owing CRS reports provide overview information on FDA’s processes for approval and regulation of drugs:
•
CRS Report R41983, How FDA Approves Drugs and Regulates Their Safety and Effectiveness, by Susan Thaul.
•
CRS Report RL33986, FDA’s Authority to Ensure That Drugs Prescribed to Children Are Safe and Effective, by Susan
Thaul.
•
CRS Report R42130, FDA Regulation of Medical Devices, by Judith A. Johnson.
•
CRS Report R42508, The FDA Medical Device User Fee Program, by Judith A. Johnson.
(Note: The rest of this report has not been updated since September 1, 2011.)
This report is a primer on drug approval and regulation: it describes (1) how drugs are approved
and come to market, including FDA’s role in that process and (2) FDA and industry roles once
drugs are on the pharmacy shelves.
Legislative History of Drug Regulation
Derived from the Dutch word meaning to boast (quacken), “quack” is the word Americans have
commonly used to describe charlatans in medicine. Quacks peddled adulterated and mislabeled
medicines throughout the United States without penalty until 1906, when Congress passed the
Food and Drugs Act,1 one section of which outlawed the practice.
Over the next half-century, Congress passed two major pieces of legislation expanding FDA
authority. It passed the Federal Food, Drug, and Cosmetic Act (FFDCA)2 in 1938, requiring that
drugs be proven safe before they could be sold in interstate commerce. Then, in 1962, in the wake
of deaths and birth defects from the tranquilizer thalidomide marketed in Europe, Congress
passed the Kefauver-Harris Drug Amendments to the FFDCA,3 increasing safety provisions and
requiring that drugs be proven effective as well.
Congress has amended the FFDCA many times, leading to FDA’s current mission of assuring
Americans that the medicines they use do no harm and actually work—that they are, in other
1 Federal Food and Drug Act of 1906 (F&DA), P.L. 59-384, 1906.
2 Federal Food, Drug, and Cosmetic Act (FFDCA), P.L. 75-717, 1938. The FFDCA included a provision to repeal the
F&DA.
3 Kefauver-Harris Drug Amendments to the FFDCA, P.L. 87-781, 1962.
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words, safe and effective. In recent decades Congress has passed additional laws to boost
pharmaceutical research and development and to speed the approval of new medicines.4
FDA also regulates products other than drugs—for example, biological products, medical devices,
dietary supplements, foods, cosmetics, animal drugs, and tobacco products. Sometimes the
agency addresses issues that straddle two or more product types that the law treats differently.
Textbox 1. Examples of Drug Laws that Amended the FFDCA
•
The 1983 Orphan Drug Act, which provided incentives for pharmaceutical manufacturers to develop drugs,
biotechnology products, and medical devices for the treatment of rare diseases and conditions;
•
the 1984 Hatch-Waxman Act, a compromise balancing greater patent protection of manufacturers with quicker
public access to lower-priced generic drugs;
•
the 1992 Prescription Drug User Fee Act (PDUFA), which ushered in user fees and performance goals for faster
drug approvals;
•
the 1997 FDA Modernization Act (FDAMA), which relaxed clinical testing requirements, eased access to
experimental therapies, and awarded drugmakers six more months of marketing protection for testing drugs in
pediatric patients.
•
the 2002 Public Health Security and Bioterrorism Preparedness and Response Act, which reauthorized the
FDAMA pediatric testing provision within the 2002 Best Pharmaceuticals for Children Act (BPCA) and extended
the drug user fee law for five more years;
•
the 2003 Pediatric Research Equity Act (PREA), which required manufacturers to include pediatric assessments
in new drug applications; and
•
the 2007 Food and Drug Administration Amendments Act (FDAAA), which went beyond the anticipated
reauthorization of PDUFA, BPCA, and PREA (among other provisions) by also expanding FDA authority to
regulate drug safety.5
How FDA Approves New Drugs
To market a prescription drug in the United States, a manufacturer needs FDA approval.6 To get
that approval, the manufacturer must demonstrate the drug’s safety and effectiveness according to
criteria specified in law and agency regulations, ensure that its manufacturing plant passes FDA
inspection, and obtain FDA approval for the drug’s labeling—a term that includes all written
4 For a chronological listing of legislation relating to FDA regulation of drugs, see “Table 3. Human Drugs Statutory
Authorities in 1980 and 2007” in CRS Report RL34334, The Food and Drug Administration: Budget and Statutory
History, FY1980-FY2007, coordinated by Judith A. Johnson.
5 The Orphan Drug Act (P.L. 97-414), the Hatch-Waxman Act (the Drug Price Competition and Patent Term
Restoration Act of 1984, P.L. 98-417), PDUFA (P.L. 102-571), FDAMA (P.L. 105-115), the Best Pharmaceuticals for
Children Act (107-109), the Public Health Security and Bioterrorism Preparedness Act (P.L. 107-188), and the FDA
Amendments Act of 2007 (FDAAA, P.L. 110-85).
6 FDA-approved drugs are designated by law into only two categories: prescription and nonprescription (also referred
to as over-the-counter). No drug was prescription-only until the 1951 Humphrey-Durham amendments [P.L. 82-215,
the Food, Drug, and Cosmetics Act Amendments Act, 1951], which stated, “A drug intended for use by man which ...
because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures
necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such
drug;” (FFDCA 503(b)(1).
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material about the drug, including, for example, packaging, prescribing information for
physicians, and patient brochures.
The approval process begins before the law requires FDA involvement. Figure 1 illustrates a
product’s timeline both before and during FDA involvement.
The research and development process for a finished drug usually begins in the laboratory. Basic
research is often conducted or funded by the federal government.7 When basic research yields an
idea that someone identifies as a possible drug component, government or private research groups
focus attention on a prototype design. At some point, private industry (either a large, established
company or a newer, smaller, start-up company) continues to develop the idea, eventually testing
the drug in animals. When the drug is ready for testing in humans, the FDA must get involved.
Figure 1. Drug Development Path
Source: Created by CRS.
Note: FDA = Food and Drug Administration. IND = investigational new drug application. NDA = new drug
application.
The Standard Process of Drug Approval
The four FDA steps leading to the agency’s approval of a new drug for marketing in the United
States are described below. This report describes the process for a new drug. For a generic drug—
one that is chemically and therapeutically identical to an already approved drug—the process is
abbreviated.8
7 CRS Report R41705, The National Institutes of Health (NIH): Organization, Funding, and Congressional Issues, by
Judith A. Johnson and Pamela W. Smith, provides a definition (“basic research is research in the fundamental medical
sciences, sometimes called lab or bench research, while clinical research involves patients”) and a discussion of its
relationship to drug development and clinical research.
8 FDA, “Abbreviated New Drug Application (ANDA): Generics,” http://www.fda.gov/Drugs/
DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/
AbbreviatedNewDrugApplicationANDAGenerics/default.htm.
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Investigational New Drug (IND) Application
Except under very limited circumstances, FDA requires data from clinical trials—formally
designed, conducted, and analyzed studies of human subjects—to provide evidence of a drug’s
safety and effectiveness. Before testing in humans—called clinical testing—the drug’s sponsor
(usually its manufacturer) must file an investigational new drug (IND) application with FDA. The
IND includes information about the proposed clinical study design, completed animal test data,
and the lead investigator’s qualifications. It must also include the written approval of an
Institutional Review Board, which has determined that the study participants will be made aware
of the drug’s investigative status and that any risk of harm will be necessary, explained, and
minimized. The application must include an “Indication for Use” section that describes what the
drug does and the clinical condition and population for which the manufacturer intends its use.
Trial subjects should be representative of that population. The FDA has 30 days to review an IND
application. Unless FDA objects, a manufacturer may then begin clinical testing.
Clinical Trials
With IND status, researchers test in a small number of human volunteers the safety they had
demonstrated in animals. These trials, called Phase I clinical trials, attempt, in FDA’s words, “to
determine dosing, document how a drug is metabolized and excreted, and identify acute side
effects.” If the sponsor considers the product still worthy of investment, it continues with Phase II
and Phase III clinical trials. Those trials gather evidence of the drug’s efficacy and effectiveness
in larger groups of individuals with the particular characteristic, condition, or disease of interest,
while continuing to monitor safety.9
Textbox 2. Safety, Efficacy, and Effectiveness
Safety is often measured by toxicity testing to determine the highest tolerable dose or the optimal dose of a drug
needed to achieve the desired benefit. Studies that look at safety also seek to identify any potential adverse effects
that may result from exposure to the drug. Efficacy refers to whether a drug demonstrates a health benefit over a
placebo or other intervention when tested in an ideal situation, such as a tightly controlled clinical trial. Effectiveness
describes how the drug works in a real-world situation. Effectiveness is often lower than efficacy because of
interactions with other medications or health conditions of the patient, sufficient dose or duration of use not
prescribed by the physician or fol owed by the patient, or use for an off-label condition that had not been tested.10
New Drug Application (NDA)
Once a manufacturer completes the clinical trials, it submits a new drug application (NDA) to
FDA’s Center for Drug Evaluation and Research (CDER). The NDA contains not only the clinical
trial results, but also information about the manufacturing process and facilities, including quality
control and assurance procedures. The application includes a product description (chemical
formula, specifications, pharmacodynamics, and pharmacokinetics11); the indication (specifying
9 FDA, “Inside Clinical Trials: Testing Medical Products in People; What Is a Clinical Trial?” Information for
Consumers, http://www.fda.gov/Drugs/ResourcesForYou/Consumers/ucm143531.htm.
10 A resource for epidemiologic terms is A Dictionary of Epidemiology, Fifth Edition, Miquel Porta, editor, Oxford
University Press, 2008.
11 “Pharmacokinetic [PK] studies provide information on what the body does to a drug. More specifically, it covers
how a drug is absorbed, distributed, metabolized and eliminated by the body. Pediatric PK studies are generally
(continued...)
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one or more diseases or conditions for which the drug would be used and the population who
would use it); labeling; manufacturing description; and a proposed Risk Evaluation and
Mitigation Strategy (REMS), if appropriate.
During the NDA review, CDER officials evaluate the drug’s safety and effectiveness data,
analyze samples, inspect the facilities where the finished product will be made, and check the
proposed labeling for accuracy.
FDA Review
FDA considers three overall questions in its review of an NDA:12
• Whether the drug is safe and effective in its proposed use, and whether the
benefits of the drug outweigh the risks.
• Whether the drug’s proposed labeling (package insert) is appropriate, and what it
should contain.
• Whether the methods used to manufacture the drug and the controls used to
maintain the drug’s quality are adequate to preserve the drug’s identity, strength,
quality, and purity.
FDA scientific and regulatory personnel consider the application and prepare written assessments
in several categories, including Medical, Chemistry, Pharmacology, Statistical, Clinical,
Pharmacology, Biopharmaceutics, Risk Assessment and Risk Mitigation, Proprietary Name, and
Label and Labeling.
The FFDCA requires “substantial evidence” of drug safety and effectiveness.13 FDA has
interpreted this term to mean that the manufacturer must provide at least two adequate and well-
controlled Phase III clinical studies, each providing convincing evidence of effectiveness.14 The
agency, however, exercises flexibility in what it requires as evidence.15 As its regulations describe
in detail, FDA can assess safety and effectiveness in a variety of ways, relying on combinations of
studies by the manufacturer and reports of other studies in the medical literature.16 For many
NDAs, FDA convenes advisory panels of experts to review the clinical data.17 While not bound
(...continued)
performed in patients, and focus on the measurement of drug in blood, urine, or in other body fluids or tissues....
Pharmacodynamic [PD] studies provide information on what a drug does to the body. PD examines how a drug works
in the body and the amount of drug needed to provide an effect” (FDA, “Pediatric Studies Characteristics,”
http://www.fda.gov/ScienceResearch/SpecialTopics/PediatricTherapeuticsResearch/ucm221758.htm).
12 FDA, “New Drug Application (NDA): Introduction,” http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.htm.
13 FFDCA (P.L. 75-717, 1938), §505(c) and (d).
14 The requirements for adequate and well-controlled studies are given in 21 CFR 314.126.
15 See FDA, Guidance for Industry: Providing Clinical Evidence of Effectiveness for Human Drug and Biological
Products, CDER and CBER, May 1998, at http://www.fda.gov/cder/guidance/1397fnl.pdf.
16 The requirements for adequate and well-controlled studies are given in 21 CFR 314.126.
17 FDA has established various advisory committees whose members advise the agency. Most are named and have
duties in relation to an area of medicine (such as the Cardiovascular and Renal Drugs Advisory Committee), and some
reflect cross-cutting issues (such as the Pediatric Advisory Committee and the Drug Safety and Risk Management
Advisory Committee); see FDA, “Committees & Meeting Materials,” http://www.fda.gov/AdvisoryCommittees/
(continued...)
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by an advisory panel’s recommendation regarding approval, FDA usually follows advisory panel
recommendations.
FDA approves an application based on its review of the clinical and nonclinical research evidence
of safety and effectiveness, manufacturing controls and facility inspection, and labeling. An
approval may include specific conditions, such as required post-approval studies (or post-
approval clinical trials, sometimes referred to as Phase IV clinical trials) that the sponsor must
conduct after marketing begins. An approval may also include restrictions on distribution,
required labeling disclosures, or other elements of Risk Evaluation and Mitigation Strategies
(REMS), which are described below in the section titled “How FDA Regulates Approved Drugs.”
FDA has 180 days to review an NDA. If it finds deficiencies, such as missing information, the
clock stops until the manufacturer submits the additional information. If the manufacturer cannot
respond to FDA’s request (e.g., if a required study has not been done, making it impossible to
evaluate safety or effectiveness of the drug), the manufacturer may voluntarily withdraw the
application. If and when the manufacturer is able to provide the information, the clock resumes
and FDA continues the review.
When FDA makes a final determination, it sends the applicant a “complete response letter.”18 If
FDA decides to not approve an application, regulations state that the letter must describe the
specific deficiencies the agency identified and recommend ways for the applicant to make the
application viable. An unsuccessful applicant may request a hearing.19 Regulations identify the
reasons for which FDA can reject an NDA, which include problems with clinical evidence of
safety and effectiveness for its proposed use, manufacturing facilities and controls, labeling,
access to facilities or testing samples, human subject protections, and patent information.20
Special Mechanisms to Expedite
the Development and Review Process
Not all reviews and applications follow the standard procedures. For drugs that address unmet
needs or serious diseases or conditions, FDA regularly uses three formal mechanisms to expedite
the development and review process:21
(...continued)
CommitteesMeetingMaterials/default.htm.
18 Until July 2008, FDA responded to applicants with a letter indicating whether the application was “approved,”
“approvable” (pending specified additions, such as more testing, made to the application), or “unapprovable” (FDA,
“Action Packages for NDAs and Efficacy Supplements,” MAPP 6020.8, Manual of Policies and Procedures, Office of
New Drugs, Center for Drug Evaluation and Research, Effective Date: November 13, 2002, http://www.fda.gov/
downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/UCM082010.pdf). In July 2008, FDA
issued the rules regarding the “complete response letter ” (FDA, 21 CFR Parts 312, 314, 600, and 601 [Docket No.
FDA–2004–N–0510] (formerly Docket No. 2004N–0267), “Applications for Approval to Market a New Drug;
Complete Response Letter; Amendments to Unapproved Applications; Final rule,” Federal Register, v. 73, no. 133,
July 10, 2008, pp. 39588- 39611).
19 21 CFR 314.110. Complete response letter to the applicant.
20 21 CFR 314.125. Refusal to approve an application.
21 For a discussion of their use, intended effects, and statutory and regulatory bases, see CRS Report RS22814, FDA
Fast Track and Priority Review Programs, by Susan Thaul.
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• Accelerated approval22 and animal efficacy approval23 change what is needed in
an application.
• Fast track applications24 affect the timing and smoothness of the application
process.
• Priority review25 affects the timing of the review, not the process leading to
submission of an application. (See Textbox 3 for brief descriptions of these
mechanisms.)
Textbox 3. Accelerated Approval, Fast Track, and Priority Review
Accelerated approval. FDA regulations allow “accelerated approval” of a drug or biologic product that provides a
“meaningful therapeutic benefit ... over existing treatments.” The rule covers two situations. The first allows approval
to be based on clinical trials that, rather than using standard outcome measures such as survival or disease
progression, use “a surrogate endpoint that is reasonably likely ... to predict clinical benefit.” The second situation
addresses drugs whose use FDA considers safe and effective only under set restrictions that could include limited
prescribing or dispensing. FDA usual y requires postmarketing studies of products approved this way.
Fast track. The Food and Drug Administration Modernization Act of 1997 (FDAMA, P.L. 105-115) directed the
Secretary to create a mechanism whereby FDA could designate as “Fast Track” certain products that meet two
criteria. First, the product must concern a serious or life-threatening condition; second, it must have the potential to
address an unmet medical need. Once FDA grants a Fast Track designation, it encourages the manufacturer to meet
with the agency to discuss development plans and strategies before the formal submission of an NDA. Such early
interaction can help clarify elements of clinical study design and presentation that if absent at NDA submission could
delay approval decisions. However, FDA makes similar interactions available to any sponsor who seeks FDA
consultation throughout the stages of drug development.
Priority review. Unlike Fast Track or Accelerated Approval, the Priority Review process begins only when a
manufacturer officially submits an NDA. Priority Review, therefore, does not alter the timing or content of steps
taken in a drug’s development or testing for safety and effectiveness. Although Priority Review is not explicitly
required by law, FDA has established it in practice, and various statutes, such as the Prescription Drug User Fee Act
(PDUFA), refer to and sometimes require it. When FDA determines that a product would address an unmet need, it
places it through Priority Review. That designation results in an average turnaround time (from completed application
to approval decision) of approximately 6 months, rather than the 10-month average for Standard Review.
22 21 CFR 314 Subpart H.
23 The Animal Efficacy Rule allows manufacturers to submit effectiveness data from animal studies as evidence to
support applications of certain new products “when adequate and well-controlled clinical studies in humans cannot be
ethically conducted and field efficacy studies are not feasible” (21 CFR 314 Subpart I and 21 CFR 601 Subpart H).
24 FFDCA §506 [21 USC §356]. FDA, “Guidance for Industry: Fast Track Drug Development Programs—Designation,
Development, and Application Review,” Center for Drug Evaluation and Research and Center For Biologics
Evaluation and Research, January 2006.
25 FDA Center for Drug Evaluation and Research, Manual of Policies and Procedures 6020.3, revised July 18, 2007;
FDA Center for Biologics Evaluation and Research, Manual of Standard Operating Procedures and Policies 8405,
revised September 20, 2004; FDA, “FY 2010 Performance Report to the President and Congress for the Prescription
Drug User Fee Act,” http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports
/PerformanceReports/ PDUFA/UCM243358.pdf; and FDA, “Fast Track, Accelerated Approval and Priority Review,”
http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/SpeedingAccesstoImportantNewTherapies/
ucm128291.htm. Congress used the Priority Review mechanism to encourage the development of treatments for
tropical diseases; FFDCA §524 allows the Secretary to issue a transferable priority review voucher “to the sponsor of a
tropical disease product application that entitles the holder of such voucher to priority review of a single human drug
application.”
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Other options fit limited situations and support shorter times from idea to approved public use.
For example, the Project BioShield Act of 2004 allows the HHS Secretary to authorize in certain
circumstances the emergency use of products that do not yet have FDA approval.26
How FDA Regulates Approved Drugs
FDA’s role in ensuring a drug’s safety and effectiveness continues after the drug is approved and
it appears on the market. FDA acts through its postmarket regulatory procedures after a
manufacturer has sufficiently demonstrated a drug’s safety and effectiveness for a defined
population and specified conditions and the drug is FDA-approved. Manufacturers must report all
serious and unexpected adverse reactions to FDA, and clinicians and patients may do so. FDA
oversees surveillance, studies, labeling changes, and information dissemination, among
other tasks.
FDA Offices Responsible for Drug Postapproval Regulation
Offices throughout FDA, mostly in the Center for Drug Evaluation and Research, address the
safety of the drug supply. The primary focus of activity is the Office of Surveillance and
Epidemiology (OSE), formerly named the Office of Drug Safety. Other organizational units
evaluating safety issues include the Office of Regulatory Affairs; the Division of Drug Marketing,
Advertising and Communications; the Division of Drug Information; and the Division of
Compliance Risk Management and Surveillance.
OSE uses reports of adverse events that consumers, clinicians, or manufacturers believe might be
drug-related to “identify drug safety concerns and recommend actions to improve product safety
and protect the public health.”27 FDA activities regarding drug safety once a drug is on the market
(postmarket or postapproval period) are diverse. FDA staff
• look for “signals” of safety problems of marketed drugs by reviewing adverse
event reports through the MedWatch program;
• review studies conducted by manufacturers when required as a condition of
approval;
• monitor relevant published literature;
• conduct studies using computerized databases;
• review errors related to similarly named drugs;
• conduct communication research on how to provide balanced benefit and risk
information to clinicians and consumers; and
• remain in contact with international regulatory bodies.
26 21 USC 360bbb-3.
27 FDA, “Office of Surveillance and Epidemiology (OSE),” CDER, http://www.fda.gov/AboutFDA/CentersOffices/
CDER/ucm106491.htm.
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Among the many advisory groups that work with FDA, two have roles specific to drug safety.
The Drug Safety and Risk Management Advisory Committee met for the first time with this name
in July 2002.28 Members, appointed by the commissioner, represent areas of expertise in science,
risk communication, and risk management. The group “advises the Commissioner or designee in
discharging responsibilities as they relate to helping to ensure safe and effective drugs for human
use.” 29 One member may be designated to represent consumer concerns; one non-voting member
may represent industry concerns.30
FDA created the Drug Safety Oversight Board as part of its 2005 Drug Safety Initiative and later
required by FDAAA.31 Its members include both FDA personnel and representatives of the
Agency for Healthcare Research and Quality, the Centers for Disease Control and Prevention, the
Department of Defense, the Indian Health Service, the National Institutes of Health, and the
Department of Veterans Affairs.32 Its roles are to advise the CDER director “on the handling and
communicating of important and often emerging drug safety issues” and to provide “a forum for
discussion and input about how to address potential drug safety issues.”33
FDA Drug-Regulation Activities
FDA postmarket drug safety and effectiveness activities address aspects of drug production,
distribution, and use. This section highlights nine activities that have traditionally interested
Congress in relation to drug safety and effectiveness: product integrity, labeling, reporting,
surveillance, drug studies, risk management, information dissemination, off-label use, and direct-
to-consumer advertising.
28 A predecessor group was the Drug Abuse Advisory Committee (http://www.fda.gov/OHRMS/DOCKETS/98fr/
071102f.htm).
29 FDA, “Drug Safety and Risk Management Advisory Committee Charter,” http://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/ucm094886.htm.
30 FDA, “Drug Safety and Risk Management Advisory Committee,” http://www.fda.gov/AdvisoryCommittees/
CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/default.htm. Holding joint
meetings with disease-focused advisory committees (e.g., Anesthetic and Life Support Drugs; Arthritis; Endocrinologic
and Metabolic Drugs; and Pulmonary-Allergy Drugs Advisory Committees), the Drug Safety and Risk Management
Advisory Committee considered varied topics in 2010, including new drug applications for the treatment of
fibromyalgia; the relief of moderate to severe pain where the use of an immediate-release, orally administered, opioid
analgesic tablet is appropriate; the results of studies evaluating the addition of niacin, added for the purpose of reducing
the misuse of oxycodone; and a non-steroidal anti-inflammatory drug product indicated for the treatment of the signs
and symptoms of osteoarthritis. Other topics included a proposed Risk Evaluation and Mitigation Strategy for
extended-release and long-acting opioid analgesics; the cardiovascular safety of a drug approved for blood glucose
control in adults with type 2 diabetes mellitus; and the design of medical research studies to evaluate serious asthma
outcomes with the use of the class of asthma medications known as long-acting beta-2 adrenergic agonists.
31 FDAAA §901(b) added FFDCA §505-1(j).
32 FDA, “Drug Safety Oversight Board,” http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm082129.htm.
Examples of topics the DSOB considered in 2010 are proton pump inhibitors and the risk of fractures; gadolinium-
based contrast agents and renal adverse events and anaphylaxis; CT scans, radiation exposure, and cancer risk;
bisphosphonates and a potential risk of atypical femoral shaft fracture; opioid REMS for extended-release and long-
acting products; genetic testing for cisplatin-induced ototoxicity; issues surrounding the heparin potency change; how
to communicate FDA’s updated recommendations about long acting beta agonists (LABAs); and the propoxyphene
safety issue.
33 FDA, “Drug Safety Oversight Board,” http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm082129.htm.
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Product Integrity
Ensuring product integrity34 was the key task of FDA’s predecessors. It is still an essential
concern of the agency. The FFDCA dictates requirements that manufacturers must meet, and it
allows FDA to regulate manufacturing facilities, warehouses, and transportation plans.35 For
example, among many other requirements, the FFDCA requires (1) annual registration of “any
establishment in any State engaged in the manufacture, preparation, propagation, compounding,
or processing of a drug or drugs”;36 (2) submission of lists of products, including ingredients and
labeling;37 (3) inspection of drug lots for packaging and labeling control;38 and (4) “sampling and
testing of in-process materials and drug products.”39
One way to track product integrity is a chain-of-custody document, defined by an FDA official as
a record of “the movement of the drug from the place of manufacture through the U.S. drug
supply chain to the final dispenser.”40 Such a document would allow someone to take a drug off
the pharmacy shelf and determine where it was mixed and manufactured, what ships or trucks
transported it, and who was responsible each time the finished product or its ingredients changed
hands. Since 1987, Congress has required that a statement accompany each transfer of a finished
drug, identifying the date and entity of each prior transfer (sale, purchase, transfer).41 Although
implementing regulations have been delayed in court cases, manufacturers do create chain-of-
custody documents and FDA has presented its requirements in a Compliance Policy Guide.42
FDAAA added that the Secretary must develop standards and identify and validate effective
technologies to secure the drug supply chain against counterfeit, diverted, subpotent, standard,
adulterated, misbranded, or expired drugs. FDAAA directed the Secretary, in developing those
standards, to address promising technologies, such as radiofrequency identification technology,
nanotechnology, encryption technologies, and other track-and-trace technologies.
FDAAA also mandated that the Secretary develop a standardized numerical identifier to be
applied to a prescription drug at the point of manufacturing and repackaging; undertake enhanced
and joint enforcement activities with other federal and state agencies; and establish regional
34 FFDCA section titles refer to “adulterated” (§501) and “misbranded” (§502) drugs.
35 Although this discussion focuses on U.S. facilities, the FFDCA includes registration and product listing requirements
for foreign facilities involved with drugs FDA-approved for sale in the United States. FDA and others are looking at
how the agency carries out its regulatory responsibilities in an increasingly global industry (see, for example, FDA,
“Report to Committee on Appropriations: Report on FDA’s Approach to Medical Product Supply Chain Safety in
response to the Joint Explanatory Statement to accompany H.R. 1105, the Omnibus Appropriations Act, 2009,” July
2009, http://www.fda.gov/downloads/Safety/SafetyofSpecificProducts/UCM184049.pdf).
36 FFDCA §510(b) [21 USC 310(b)] and 21 CFR Part 207.
37 FFDCA §510(j) [21 USC 360(j)] and 21 CFR Part 207.
38 21 CFR 211.134.
39 21 CFR 211.110.
40 Statement of Randall W. Lutter, Ph.D., Associate Commissioner for Policy and Planning, Food and Drug
Administration, before the Subcommittee on Criminal Justice, Drug Policy, and Human Resources, House Committee
on Oversight Government Reform, “Pharmaceutical Supply Chain Security,” July 11, 2006, http://www.fda.gov/
NewsEvents/Testimony/ucm111440.htm.
41 Prescription Drug Marketing Act of 1987 (PDMA).
42 FDA, “Compliance Policy Guide: CPG Sec. 160.900 Prescription Drug Marketing Act—Pedigree Requirements
under 21 CFR Part 203,” http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/
ucm073857.htm.
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capabilities for validation and inspection. In March 2010, FDA published guidance on
standardized numerical identification.43
Labeling
Adverse events sometimes warrant regulatory actions such as labeling changes, letters to health
professionals, or, once in a great while, a drug’s withdrawal from the market. The regulations
require a company to make the label change as soon as there is reasonable evidence—not proof—
of an association with serious hazard.44
Textbox 4. Example: Same Data, Different Decisions
The art and science of these judgments result, at times, in different decisions by different reviewers. An interesting
example appeared on FDA’s website on February 9, 2005, regarding Adderall, a stimulant medication used to treat
attention deficit disorder. On the basis of data from U.S. reporting systems, Canadian authorities chose to stop sales,
whereas U.S. authorities chose to alert the public but not to restrict sales at that time.45 One year later, however, the
FDA Drug Safety and Risk Management Advisory Committee reviewed data that “suggested stimulants might increase
the risks of strokes and serious arrhythmias in children and adults” and recommended that FDA “require
manufacturers to provide written guides to patients and place prominent warnings on drug labels describing these
risks.”46
Researchers debate the effectiveness of labeling. This is particularly true when it comes to black-
box warnings, so called because they are bordered in black to signify their importance. A 2006
study of physician compliance with the warnings found that when prescribing drugs with black-
box warnings, doctors violated those warnings in 7% of prescriptions.47
FDA can institute label changes based on information it gathers from mandatory industry reports
to its Adverse Events Reporting System (AERS), manufacturer-submitted postmarket studies, and
voluntary adverse event reports from clinicians and patients. When a manufacturer believes data
from original or published studies support a new use for a drug, a manufacturer itself can initiate
a label change to support a new marketing claim. The manufacturer submits to FDA the new data
in a supplement to the original NDA and requests that FDA allow it to modify the labeling. In
addition, if a manufacturer wants to strengthen warning labeling, it may do so before FDA
approves that supplemental application.48 With FDAAA, the Secretary may, upon learning of new
relevant safety information, require a labeling change.
43 FDA, “Guidance for Industry: Standards for Securing the Drug Supply Chain - Standardized Numerical
Identification for Prescription Drug Packages,” Office of the Commissioner (OC), Center for Drug Evaluation and
Research (CDER), Center for Biologics Evaluation and Research (CBER), Office of Regulatory Affairs (ORA), March
2010, http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM206075.pdf.
44 21 CFR 201.57(e).
45 FDA, “Statement on Adderall,” FDA Statement, February 9, 2005, at http://www.fda.gov/bbs/topics/news/2005/
NEW01156.html, and FDA, Public Health Advisory for Adderall and Adderall XR, February 9, 2005, at
http://www.fda.gov/cder/drug/advisory/adderall.htm.
46 Gardiner Harris, “Warning Urged on Stimulants Like Ritalin,” New York Times, February 10, 2006; and FDA,
CDER, Draft Agenda, Drug Safety and Risk Management Advisory Committee, Gaithersburg, Md., February 9-10,
2006, at http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4202B1_03_FDA-Tab03.pdf.
47 Karen E. Lasser, Diane L. Seger, D. Tony Yu, et al., “Adherence to Black Box Warnings for Prescription
Medications in Outpatients,” Archives of Internal Medicine, vol. 166, February 13, 2006, pp. 338-344.
48 FDA, “Supplemental Applications Proposing Labeling Changes for Approved Drugs, Biologics, and Medical
(continued...)
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Labeling plays a major role in the presentation of safety and effectiveness information. Some
contend that changes in prescribing information are not enough to protect the public’s health
because, as recent questions from consumers and Members of Congress demonstrate, the labeling
language, clear to those in the drug approval business, can confuse lay readers. For example,
“Studies in children have not demonstrated effectiveness” represents a different state of
knowledge than “Effectiveness in children has not been demonstrated.” The first sentence says
that researchers have looked to see whether the drug was effective and were unable to find that
evidence—although the drug still could be effective in children, the study design or analysis did
not see that. The second sentence, however, does not clarify whether any study had been done.
In January 2006, FDA issued a final rule, final guidance, and supporting documents to overhaul
the labeling requirements for prescription drugs.49
Reporting
Once FDA approves a drug, it monitors safety. Manufacturers must report all serious and
unexpected adverse reactions to FDA’s Adverse Events Reporting System (AERS) within 15 days
of becoming aware of them (21 CFR 310.305). Health professionals and patients may report
adverse reactions to FDA’s MedWatch reporting system at any time. FDA adds MedWatch
submissions to the AERS database.50 A manufacturer must also report the results of clinical
studies it conducts on its approved products, along with what it knows about others’ research and
publications.51
Surveillance
FDA gathers information about possible adverse reactions to the products it has approved for U.S.
use. Under the authority granted by FFDCA, FDA requires manufacturers to report adverse
events. It also provides a procedure for consumers and physicians to voluntarily report their
concerns about drugs. The agency collects those reports through MedWatch and uses its Adverse
Event Reporting System (AERS)52 to store and analyze them. Because some events may occur
after the use of a drug for reasons unrelated to the it, FDA scientists review the events to assess
which ones may indicate a drug problem. They then use information gleaned from the
surveillance data to determine a course of action. They might recommend a change in drug
(...continued)
Devices; Final rule,” Federal Register, v. 73, no. 164, August 22, 2008, pp. 49603-49610.
49 See the FDA News release for links to various documents, at http://www.fda.gov/NewsEvents/Newsroom/
PressAnnouncements/2006/ucm108579.htm.
50 FDA presents quarterly summaries of AERS data on its website (FDA, “Adverse Event Reporting System (AERS)
Statistics,” http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/
ucm070093.htm). The agency also makes raw AERS data available to the public, although it notes that “[U]sers of
these files need to be familiar with creation of relational databases using applications such as ORACLE®, Microsoft
Office Access, MySQL® and IBM DB2 or the use of ASCII files with SAS® analytic tools. ... A simple search of
AERS data cannot be performed with these files by persons who are not familiar with creation of relational databases”
(FDA, “The Adverse Event Reporting System (AERS): Latest Quarterly Data Files,” http://www.fda.gov/Drugs/
GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/ucm082193.htm).
51 FFDCA §505(k).
52 FDA, “MedWatch: The FDA Safety Information and Adverse Event Reporting Program,” http://www.fda.gov/
Safety/MedWatch/default.htm; and FDA “Adverse Event Reporting System (AERS),” http://www.fda.gov/Drugs/
InformationOnDrugs/ucm135151.htm.
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labeling to alert users to a potential problem, or, perhaps, to require the manufacturer to study the
observed association between the drug and the adverse event.
Unlike planned studies with hypotheses to support or refute, for which researchers gather
information, most surveillance activities are characterized as passive, in that the information is
submitted by others.53 The agency only learns of an adverse event when someone reports one.
FDA is aware of the limitations of that approach. The reported event may signal a problem with
the drug or be unrelated but have occurred coincident with the dosing. Other actual drug effects
may be unrecognized as such and consequently not be reported. In addition, it is difficult to
interpret the extent of a problem without knowing how many people took a specific drug.
In 2008, both recognizing these limitations and responding to a requirement in FDAAA to create
and maintain a Postmarket Risk Identification and Analysis System,54 FDA began work on its
Sentinel Initiative to move from its predominantly passive surveillance system to an active one.
Building on surveillance activities already in place, and using evolving computer technology,
FDA has started to develop an infrastructure that uses data from public and private sources,
protects confidentiality, and expands its information base. By setting up the Sentinel System to
coordinate many different automated data systems, FDA aims to better detect safety signals,
analyze data to understand them, and identify strategies to fix the problem.55
Drug Studies
After a drug is on the market, FDA can recommend and ask product sponsors to conduct studies,
but in only limited situations does the law authorize FDA to require studies in the postapproval
period. Two sets of situations—distinguished by when the requirement is set—involve required
postapproval studies: when a requirement is attached to the initial approval of the drug and when
FDA informs the sponsor of a required study once a drug is on the market.
Postmarket Studies Required upon Drug Approval
Accelerated Approval. When FDA grants accelerated approval, it attaches a postmarket study
requirement to that approval. Regulations state, “Approval under this section will be subject to
the requirement that the applicant study the drug further, to verify and describe its clinical benefit,
where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the
observed clinical benefit to ultimate outcome.”56
53 CDC describes four types of surveillance methods, with the passive method’s being predominant. “The term passive
is used to convey the idea that health authorities take no action while waiting for report forms to be submitted” (CDC,
“Methods of Surveillance,” Program Operations Guidelines for STD Prevention, Surveillance and Data Management,
August 16, 2007, http://www.cdc.gov/std/program/surveillance/4-PGsurveillance.htm#passive).
54 FDAAA §905(a) amended FFDCA §505(k) to require the Secretary to, among other things, “use electronic health
data for risk identification and analysis; provide standardized reporting of adverse event data; and use federal, private,
and other data sources to conduct active adverse event surveillance and identify trends and patterns.” A fuller
description is in CRS Report RL34465, FDA Amendments Act of 2007 (P.L. 110-85), by Erin D. Williams and Susan
Thaul.
55 Sentinel Initiative, http://www.fda.gov/Safety/FDAsSentinelInitiative/ucm203500.htm, and http://www.fda.gov/
Safety/FDAsSentinelInitiative/default.htm, FDA, “The Sentinel Initiative: A National Strategy for Monitoring Medical
Product Safety,” May 2008, http://www.fda.gov/Safety/FDAsSentinelInitiative/ucm089474.htm and
http://www.fda.gov/downloads/Safety/FDAsSentinelInitiative/UCM124701.pdf.
56 21 CFR 314.510.
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Animal Efficacy. When FDA grants approval based on its animal efficacy rule, it attaches a
postmarket study requirement to that approval. The Animal Efficacy Rule allows manufacturers
to submit effectiveness data from animal studies as evidence to support applications of certain
new products “when adequate and well-controlled clinical studies in humans cannot be ethically
conducted and field efficacy studies are not feasible.”57 The regulations state,
The applicant must conduct postmarketing studies, such as field studies, to verify and
describe the drug’s clinical benefit and to assess its safety when used as indicated when such
studies are feasible and ethical. Such postmarketing studies would not be feasible until an
exigency arises.… Applicants must include as part of their application a plan or approach to
postmarketing study commitments in the event such studies become ethical and feasible.58
Pediatric Assessments. When FDA approves a drug for which it has deferred the required
pediatric assessment, it attaches a postmarket pediatric assessment requirement to that approval.
With the Pediatric Research Equity Act (PREA, P.L. 108-155, reauthorized in P.L. 110-85),
Congress required manufacturers to submit a pediatric assessment with each submission of an
application to market a new active ingredient, new indication, new dosage form, new dosing
regimen, or new route of administration.59 The law specified situations in which the Secretary
might defer or waive the pediatric assessment requirement. For a deferral, an applicant must
include a timeline for completion of studies. The Secretary must review each approved deferral
annually, for which the applicant must submit evidence of documentation of study progress.
Postmarket Studies Required After Drug Approval
Pediatric Assessment. PREA allows the Secretary to require that the manufacturer of an
approved drug submit a pediatric assessment in certain circumstances.60
Based on New Information Available to Secretary. The Secretary, under specified conditions
after a drug is on the market, may require a study or a clinical trial.61 The Secretary may
determine the need for such a study or trial based on newly acquired information. To require a
postapproval study or trial, the Secretary must determine that (1) other reports or surveillance
would not be adequate and (2) the study or trial would assess a known serious risk or signals of
serious risk, or identify a serious risk. The law directs the Secretary regarding dispute resolution
procedures.
Risk Management
With authority under the FFDCA or by practice, FDA has long implemented various tools in its
attempt to ensure that the drugs it has approved for marketing in the United States are safe and
effective for their intended and approved uses. Although the agency requires certain actions of the
57 21 CFR 314 Subpart I and 21 CFR 601 Subpart H.
58 21 CFR 314.610.
59 PREA provisions are generally codified in FFDCA §505B [21 USC 355c] Research Into Pediatric Uses for Drugs
and Biological Products. See CRS Report RL33986, FDA’s Authority to Ensure That Drugs Prescribed to Children Are
Safe and Effective, by Susan Thaul, for a description of the law’s requirements and a discussion of the issues.
60 FFDCA §505B [21 USC 355c].
61 These provisions are in FFDCA §505(o) [21 USC 355(o)] New Drugs; Postmarket studies and clinical trials;
labeling.
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manufacturers62 of all approved drugs, it deems additional actions appropriate for specific drugs
or specific circumstances surrounding a drug’s use. Some of those actions are risk-management
processes to identify and minimize risk to patients. The FDA Manual of Policies and Procedures
notes that risk management attempts to “minimize [a drug’s] risks while preserving its benefits.”63
In that 2005 document, which is still in effect, FDA described its approach to risk management as
“an iterative process” that includes both risk assessment and risk minimization. Actions available
to FDA include
• education and outreach (e.g., new professional labeling, patient-oriented labeling,
public notices);
• guides to prescribing, dispensing, or use (e.g., informed consent, program
enrollment, practitioner certification, special packaging, and limited refills);
• restricted access (e.g., registration of physicians, pharmacists, or patients, and
documentation of laboratory tests before dispensing); and
• suspension or termination of product marketing.64
Textbox 5. Balancing Risks and Benefits
The balance of a drug’s risks and benefits is not always clear. For example, FDA implemented a risk-minimization plan
for Accutane (isotretinoin), a drug that treats a severe type of acne and carries with it a risk of birth defects and
possible suicidal actions. Some clinicians objected to what they felt were onerous prescribing requirements, saying
that those requirements serve to deny the drug to individuals who need it.65 FDA allowed an exception, for example,
for oncologists prescribing isotretinoin for cancer treatment.66
The Food and Drug Administration Amendments Act of 2007 (FDAAA, P.L. 110-85) named the
risk-management process the Risk Evaluation and Mitigation System (REMS) and expanded the
risk-management authority of FDA.67 FDA practice has long included most of the elements that a
REMS may include. FDAAA gave FDA, through the REMS process, the authority for structured
follow-through, dispute resolution, and enforcement.68
62 The Federal Food, Drug, and Cosmetic Act refers to the sponsor of an application or the holder of an approved
application. Because that entity is often the product’s manufacturer or its employee, this memorandum uses the term
manufacturer throughout. Note that the manufacturer may also be the responsible person, for purposes of enforcement.
63 FDA, “Review Management: Risk Management Plan Activities in OND and ODS,” Manual of Policies and
Procedures, MAPP 6700.1, CDER (Originator: Office of New Drugs), effective September 8, 2005,
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ManualofPoliciesProcedures/ucm082058.pdf.
64 Toni Piazza-Hepp, FDA presentation: “Risk Management Programs,” at the Risk Management Public Workshop,
CDER, Washington, D.C., April 10, 2003, at http://www.fda.gov/cder/meeting/RMtranscript2.doc; and FDA, Center
for Drug Evaluation and Research 2004 Report to the Nation: Improving Public Health Through Human Drugs,
August 2005, at http://www.fda.gov/cder/reports/rtn/2004/rtn2004.pdf.
65 Gardiner Harris, “System Said to Fail to Steer Women From Acne Drug,” New York Times, February 11, 2006.
66 “FDA Announcement Re: iPledge Program for Isotretinoin,” memorandum from Richard Pazdur, Div. of Oncology
Drug Products, CDER, at http://www.ons.org/fda/documents/fda050306.pdf; and FDA, “FDA and Manufacturers of
Accutane and its Generics to Implement iPLEDGE Program on March 1, 2006,” FDA Statement, February 23, 2006, at
http://www.fda.gov/bbs/topics/NEWS/2006/NEW01324.html.
67 The REMS authority is in FFDCA §505-1 (21 USC 355-1). REMS are discussed in the presentation of Title IX
(Enhanced Authorities Regarding Postmarket Safety of Drugs) of FDAAA, pages 68-78, including Tables 12 and 13, in
CRS Report RL34465, FDA Amendments Act of 2007 (P.L. 110-85), by Erin D. Williams and Susan Thaul. FDAAA
also covered many other issues.
68 FDA has issued draft guidance documents for industry on REMS: FDA, DRAFT “Guidance for Industry: Format and
(continued...)
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FDA may require a REMS under specified conditions—including if it determines such a strategy
is necessary to ensure that the benefits of a drug outweigh its risks. It may make the requirement
when a manufacturer submits a new drug application, after initial approval or licensing, when a
manufacturer presents a new indication or other change, or when the agency becomes aware of
new information and determines a REMS is necessary.69
As part of a REMS, the Secretary may require instructions to patients and clinicians, and
restrictions on distribution or use (and a system to monitor their implementation). As listed in
FFDCA Section 505-1 (21 USC 355-1), a REMS may include the following components:
Patient information. The manufacturer must develop material “for distribution to each
patient when the drug is dispensed.”70 This could be a Medication Guide, “as provided for
under part 208 of title 21, Code of Federal Regulations (or any successor regulations),”71 or a
patient package insert.
Health care provider information. The manufacturer must create a communication plan,
which could include sending letters to health care providers; disseminate information to
providers about REMS elements to encourage implementation or explain safety protocols; or
disseminate information through professional societies about any serious risks of the drug and
any protocol to assure safe use.
Elements to assure safe use (ETASU). An ETASU is a restriction on distribution or use that
is intended to (1) allow access to those who could benefit from the drug while minimizing
their risk of adverse events and (2) block access to those for whom the potential harm would
outweigh potential benefit. By including these restrictions, FDA can approve a drug that it
otherwise would have to keep off the market because of the risk it would pose. FFDCA
Section 505-1(f)(3) lists the types of restrictions FDA could require.
• health care providers who prescribe must have particular training or experience,
or be specially certified;
(...continued)
Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS
Modifications,” Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research
(CBER), September 2009, http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM184128.pdf; and FDA, DRAFT “Guidance for Industry: Medication Guides—Distribution
Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS),” CDER and CBER, February 2011,
http://www.fda.gov/downloads/ Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM244570.pdf.
69 As of July 8, 2011, FDA had established 190 REMS for individual drugs. These are listed in FDA, “Approved Risk
Evaluation and Mitigation Strategies (REMS),” http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety
Information for PatientsandProviders/ucm111350.htm. In addition to drug-specific individual REMS, FFDCA §505-1
authorizes FDA to require a REMS for all the drugs in a pharmacological class and sets out required steps that include
public meetings (which could include the product sponsors, advisory committees, expert workshops, etc.),
announcement in the Federal Register of planned regulatory action, and public comment. FDA has completed this
process for a class-wide REMS for long-acting and extended-release opioid products (FDA, “Opioid Drugs and Risk
Evaluation and Mitigation Strategies (REMS),” http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/
ucm163647.htm; and FDA, “Questions and Answers: FDA Requires a Risk Evaluation and Mitigation Strategy
(REMS) for Long-Acting and Extended-Release Opioids,” http://www.fda.gov/Drugs/DrugSafety/
InformationbyDrugClass/ucm251752.htm).
70 FFDCA §505-1(e)(2).
71 FFDCA §505-1(e)(2)(A).
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• pharmacies, practitioners, or health care settings that dispense must be specially
certified;
• the drug must be dispensed to patients only in certain health care settings, such as
hospitals;
• the drug must be dispensed to patients with evidence or other documentation of
safe-use conditions, such as laboratory test results;
• each patient using the drug must be subject to certain monitoring; and
• each patient using the drug must be enrolled in a registry.
Any approved REMS must include a timetable of when the manufacturer will provide reports to
allow FDA to assess the effectiveness of the REMS components.
Information Dissemination
FDA maintains several communications channels through which it distributes information on
drug safety and effectiveness to clinicians, consumers, pharmacists, and the general public. These
include a monthly Drug Safety Newsletter,72 Drug Safety Communications,73 FDA Drug Safety
Podcasts,74 FDA Drug Info Rounds,75 and FDA Drug Information on Twitter.76
FDAAA required FDA to establish an Advisory Committee on Risk Communication to “advise
the Commissioner on methods to effectively communicate risks associated with” FDA-regulated
products. It also added important items to the ways that FDA informs the public about
information it has developed or gathered about drug safety and effectiveness. One required report
to Congress must address how best to communicate risks and benefits of new drugs to the public
and “the role of the risk evaluation and mitigation strategy in assessing such risks and benefits.”77
The report may also consider whether FDA, when determining the labeling of a new product or
use for a product, should alert the public that the agency’s approval is based on limited clinical
trials that may not have identified all possible risks associated with the drug—risks that may
become evident when patients use the new drug in community (rather than experimental) settings
or when the number of users becomes large enough to yield rare drug effects. Any published
direct-to-consumer prescription drug advertisement must include a statement encouraging the
reporting of negative side effects to FDA, along with a 1-800 number and website address.
Finally, FDAAA required that, after studying the issue, the Secretary report to Congress whether
that statement is appropriate for television advertisements as well. The Secretary informed
72 FDA, “Drug Safety Newsletter,” http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/default.htm and
http://www.fda.gov/Drugs/DrugSafety/DrugSafetyNewsletter/ucm096049.htm.
73 FDA, “Drug Safety Communications,” http://www.fda.gov/drugs/drugsafety/
postmarketdrugsafetyinformationforpatientsandproviders/ucm199082.htm.
74 FDA, “FDA Drug Safety Podcasts,” http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts/default.htm.
75 FDA, “FDA Drug Info Rounds,” http://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm211957.htm.
76 FDA, “FDA Drug Information (FDA_Drug_Info) on Twitter,” http://twitter.com/FDA_Drug_Info.
77 FDAAA §904. FDA submitted the report on August 31, 2009 (http://www.fda.gov/RegulatoryInformation/
Legislation/FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/
FoodandDrugAdministrationAmendmentsActof2007/FDAAAImplementationChart/default.htm).
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Congress in May 2008 that FDA is conducting a multi-year study of the content and placement of
such a statement.78
Another FDAAA requirement is for the Secretary to screen the Adverse Event Reporting System
(AERS) database on a bi-weekly basis and report quarterly on the AERS website regarding new
safety information or potential signals of a serious risk, and to report to Congress on procedures
for addressing ongoing postmarket safety issues identified by the Office of Surveillance and
Epidemiology.
Other sections of FDAAA addressed communication with the public, expert committees, and
others about agency actions and plans. The Secretary must develop and maintain a website with
extensive drug safety information, and publish a list of all authorized generic drugs. The
Secretary also must provide public access to action packages for product approval or licensure,
including certain reviews, and establish an Advisory Committee on Risk Communication.
Off-Label Use
The FFDCA prohibits a manufacturer from promoting or advertising a drug for any use not listed
in the FDA-approved labeling, which contains those claims for which FDA has reviewed safety
and effectiveness evidence.79 However, the FFDCA does not give FDA authority to regulate the
practice of medicine; that responsibility rests with the states and medical professional
associations. Once a drug is approved, a licensed physician may—except in highly regulated
circumstances—prescribe it without restriction. A prescription to an individual whose
demographic or medical characteristics differ from those indicated in a drug’s FDA-approved
labeling is called off-label use and is accepted medical practice.
Textbox 6. Examples of Off-Label Use
•
A drug that was tested in an eight-week trial may be prescribed for long-term use.
•
If a drug was tested at one dose, it may be used at higher or lower doses.
•
A drug tested in adults may be prescribed to children.
•
A drug tested for the treatment of one disease may be prescribed in an attempt to prevent another.
Off-label use presents an evaluation problem to FDA safety reviewers. Using drugs in new ways
for which researchers have not yet demonstrated safety and effectiveness can create problems that
premarket studies did not address. Manufacturers rarely design studies to establish the safety and
78 FDA, “Report to Senate Committee on Health, Education, Labor, and Pensions and the House Committee on Energy
and Commerce; Report on Study Commitment Regarding Inclusion of Toll-Free Adverse Event Reporting Number by
FDA Food and Drug Administration,” May 2008, http://www.fda.gov/downloads/RegulatoryInformation/Legislation/
FederalFoodDrugandCosmeticActFDCAct/SignificantAmendmentstotheFDCAct/FoodandDrugAdministrationAmend
mentsActof2007/FDAAAImplementationChart/UCM147012.pdf; and FDA [Docket No. FDA-2008-N-0595], “Agency
Information Collection Activities; Proposed Collection; Comment Request; Experimental Study: Toll-Free Number for
Consumer Reporting of Drug Product Side Effects in Direct-to-Consumer Television Advertisements for Prescription
Drugs,” Federal Register, vol. 73, no. 229, November 26, 2008, pp. 72058-72062. See also: FDA 21 CFR Parts 201,
208, and 209 [Docket No. FDA–2003–N–0313] (formerly Docket No. 2003N–0342) RIN 0910–AC35, “Toll-Free
Number for Reporting Adverse Events on Labeling for Human Drug Products; Final rule,” Federal Register, vol. 73,
no. 209, October 28, 2008, pp. 63886-63897.
79 The line between promotion and professional education is not always clear. See CRS Report R40458, FDA Guidance
Regarding the Promotion of Off-Label Uses of Drugs: Legal Issues, by Vanessa K. Burrows and Kathleen Ann Ruane.
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effectiveness of their drugs in off-label uses, and individuals and groups wanting to conduct such
studies face difficulties finding funding.
Direct-to-Consumer Advertising
FDA regulates the advertising of prescription drugs.80 Although the Federal Trade Commission
regulates nonprescription drug advertising, the FDA regulates the product labeling that the
nonprescription drug ads must reflect. FDAAA expanded and strengthened FDA’s enforcement
tools regarding advertising. The Secretary may now require submission of a television
advertisement for review before its dissemination. Based on this review, during which the
Secretary may consider the impact the drug might have on specific population groups (such as
older and younger individuals, or racial and ethnic minorities), the Secretary may recommend, but
not require, changes in the ad. The law authorizes the Secretary to require that an ad include
certain disclosures without which the Secretary determines that the ad would be false or
misleading. These disclosures concern information about a serious risk listed in a drug’s labeling
and the date of a drug’s approval.
FDAAA required that television and radio ads present the required information on side effects
and contraindications in a “clear, conspicuous, and neutral manner.”81 It also established civil
penalties for the dissemination of a false or misleading direct-to-consumer (DTC) advertisement.
Also, any published DTC advertisement must include the following statement printed in
conspicuous text: “You are encouraged to report negative side effects of prescription drugs to the
FDA. Visit http://www.fda.gov/medwatch, or call 1-800-FDA-1088.”82
Author Contact Information
Susan Thaul
Specialist in Drug Safety and Effectiveness
sthaul@crs.loc.gov, 7-0562
80 For an indepth discussion of this issue, see CRS Report R40590, Direct-to-Consumer Advertising of Prescription
Drugs, by Susan Thaul.
81 FFDCA §502(n) as amended by FDAAA §901(d)(3).
82 FFDCA §502(n) as amended by FDAAA §906(a).
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