Adverse Experience/Adverse Event
An Adverse Experience/Adverse Event is any adverse event associated with the use of a drug in humans, whether or not considered drug related, including the following: An adverse event occurring in the course of the use of a drug product in professional practice; an adverse event occurring from drug overdose whether accidental or intentional; an adverse event occurring from drug abuse; an adverse event occurring from drug withdrawal; and any failure of expected pharmacological action. (1)
Adverse Drug Experience/Adverse Drug Event
Adverse Drug Reaction
An Adverse Drug Reaction is an AE/ADE for which there is a reasonable possibility that the AE/ADE may have been caused by the drug. (2)
When concern about a serious risk of a drug or biological product may be related to the pharmacologic class of that product, the FDA may require a REMS to ensure that benefits outweigh risks. (3) . A class REMS encompasses a particular class or classes of drugs or biological products, whereas a REMS focuses on a specific drug or biological product. Six classes of drugs have been identified as requiring such a “class” REMS: long-acting opioids, fluoroquinolone antibiotics, anti-epileptic drugs, tumor necrosis factor (TNF) blocking drugs/inhibitors, botulinum toxins, and erythropoiesis-stimulating agents.
A Communication Plan as described in FDAAA involves risk communications to healthcare providers, such as physicians, pharmacists, nurses, physician assistants, etc. It may include some or all of the following:
sending letters to health care providers (e.g., Dear HCP letters);
disseminating educational information about the elements of the risk evaluation and mitigation strategy to encourage implementation by health care providers of components that apply to such health care providers, or to explain certain safety protocols (such as medical monitoring by periodic laboratory tests); or
disseminating information to health care providers through professional societies about any serious risks of the drug and any protocol to assure safe use. (3)
Products “deemed to have a REMS” are drugs and biological products approved/licensed with EASUs or Risk Minimization Action Plans (Risk MAPs) before FDAAA became effective on March 25, 2008. Sponsors of these products were required to resubmit a Proposed REMS to the FDA by September 21, 2008. (4,5)
Elements to Assure Safe Use (EASU)
Elements to Assure Safe Use as defined in FDAAA include:
health care providers who prescribe the drug have particular training or experience, or are specially certified;
pharmacies, practitioners, or health care settings that dispense the drug are specially certified;
the drug is dispensed to patients only in certain health care settings, such as hospitals;
the drug is dispensed to patients with evidence or other documentation of safe use conditions, such as laboratory test results;
each patient using the drug is subject to certain monitoring; or
each patient using the drug is enrolled in a registry (see section 505-1(f)(3) of the Act). (3,4)
Food and Drug Administration (FDA) Amendments Act of 2007
The FDA Amendments Act of 2007 is an amendment to the Food, Drug, and Cosmetic Act to revise and extend the user-fee programs for prescription drugs and medical devices, to enhance the postmarket authorities of the Food and Drug Administration with respect to the safety of drugs, and for other purposes. FDAAA was signed into law on September 27, 2007 and became effective on March 25, 2008. (3)
A Medication Guide contains information for patients on how to safely use a drug product. (6)
New Safety information
New Safety Information is defined in FDAAA as information derived from a clinical trial, an adverse event report, a postapproval study, or peer-reviewed biomedical literature; data derived from the postmarket risk identification and analysis system…or other scientific data deemed appropriate by the Secretary about a serious risk or an unexpected serious risk associated with use of the drug that the Secretary has become aware of (that may be based on a new analysis of existing information) since the drug was approved, since the REMS was required, or since the last assessment of the approved REMS; or the effectiveness of the approved REMS obtained since the last assessment of the strategy. (3,4)
Patient Package Insert
A Patient Package Insert contains information for patients’ understanding of how to safely use a drug product. (6) The PPI is largely being replaced by the Medication Guide as an element of a REMS.
Prescription Drug User Fee Act
The Prescription Drug User Fee Act, first enacted in 1992 (PDUFA I), provided authority for the FDA to collect fees from industry to accelerate its drug evaluation process without compromising review quality. In 1997, Congress reauthorized PDUFA (PDUFA II) under the FDA Modernization Act (FDAMA). In 2002, PDUFA was reauthorized (PDUFA III) under the Public Health Security and Bioterrorism Preparedness and Response Act. The most recent PDUFA reauthorization (PDUFA IV) was under the FDA Amendments Act of 2007 (FDAAA). (7)
Prescription Drug User Fee Act, Reauthorization IV
The Prescription Drug User Fee Act, Reauthorization IV, was granted under the FDA Amendments Act of 2007 (FDAAA) and is the most recent reauthorization of PDUFA. New funds from this reauthorization and expansion are intended to enhance and modernize FDA’s drug safety capabilities. The PDUFA IV strategy includes: 1) strengthening management and operations, 2) improving collection and analysis of adverse event data, 3) implementing epidemiology best practices, 4) expanding database acquisition and use for targeted post-marketing surveillance and epidemiology, 5) strengthening risk management and communication tools, 6) improving post-market information technology systems, and 7) increasing timely, consistent review of new drug trade names to prevent name confusion. (7)
A Proposed REMS is that portion of the REMS document that will be published on the FDA website after REMS approval at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111350.htm. It contains specific, concise information formatted according to a template with the following sections:
- Goal(s). Lists goals and objectives of the REMS.
- REMS Elements. This section is further subdivided into:
- Medication Guide or Patient Package Insert. Describes how the sponsor will comply with 21 CFR 208.24.
- Communication Plan. Describes how the sponsor will implement a plan to educate healthcare providers. Includes a listing and description of the elements of the Plan.
- Elements to Assure Safe Use (see EASU above)
- Implementation System. Describes the system to monitor and evaluate implementation for, and work to improve implementation of, EASU elements 2-4 (see EASU above).
Timetable for Submission of Assessments. Specifies the timetable for submitting assessments of the REMS to the FDA. At a minimum, assessments must be made at 18 months, 3 years, and in the seventh year after the REMS is initially approved, with dates for additional assessment if more frequent assessments are necessary to ensure the benefits of the drug continue to outweigh the risks. (3,8)
All relevant REMS materials, such as enrollment forms, informed consents, and educational and communication materials should be appended to the Proposed REMS when the document is submitted for FDA review.
Risk Evaluation and Mitigation Strategy
A Risk Evaluation and Mitigation Strategy (REMS) is a strategy and plan to manage and assess a known or potential serious risk associated with a drug or biological product. A REMS will be required if FDA finds that a REMS is necessary to ensure that the benefits of the drug or biological product outweigh the risks of the product, and FDA notifies the sponsor. A REMS can include a Medication Guide/Patient Package Insert, a Communication Plan, Elements to Assure Safe Use, and an implementation system, and must also include a timetable for assessment of the REMS. Some drug and biological products that previously were approved/licensed with Risk Minimization Action Plans (RiskMAPs) will now be deemed to have a REMS. (4)
A REMS submission consists of two parts: a Proposed REMS and a REMS Supporting Document.
REMS Supporting Document
A REMS Supporting Document includes a thorough explanation of the rationale for, and supporting information about, the content of the Proposed REMS. The document consists of the following sections:
III. Supporting Information on Proposed REMS Elements. This section is further subdivided into:
A. Additional Potential Elements
1. Medication Guide
2. Patient Package Insert
3. Communication Plan
B. Elements to Assure Safe Use, including a statement of how the elements to assure safe use will mitigate the observed safety risk
C. Implementation System
D. Timetable for Assessment of the REMS
IV. Information Needed for Assessments. (Note: the FDA may request this section be submitted with the Proposed REMS rather than with the REMS Supporting Document).
V. Other Relevant Information
All relevant REMS materials, such as enrollment forms, informed consents, and educational and communication material should be appended to the Proposed REMS when the document is submitted for FDA review. (8)
Risk Minimization Action Plan
A Risk Minimization Action Plan (RiskMAP) is a strategic safety program designed to meet specific goals and objectives in minimizing known risks of a product while preserving its benefits. (9) FDA issued guidances for developing a RiskMAP in 2005. RiskMAPs were replaced by REMS after FDAAA was signed into law in September, 2007 and became effective in March, 2008.
Serious Adverse Experience/Serious Adverse Event
A Serious Adverse Experience/Serious Adverse Event is any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered a serious adverse drug experience when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. (1)
A serious risk refers to a risk of a serious adverse drug experience. (3)
Title IX of the FDAAA
Title IX of the FDAAA refers to the section of the FDAAA concerning enhanced authorities regarding postmarket safety of drugs. Subsections of Title IX are: Subtitle A – Postmarket Studies and Surveillance, and Subtitle B – Other Provisions to Ensure Drug Safety and Surveillance. (3)
Unexpected Serious Risk
An unexpected serious risk is a serious adverse drug experience that is not listed in the labeling of a drug, or that may be symptomatically and pathophysiologically related to an adverse drug experience identified in the labeling, but differs from such adverse drug experience because of greater severity, specificity, or prevalence. (3)
- 21 CFR 314.80
- 21 CFR 312.32
- Food and Drug Administration Amendments Act of 2007 (FDAAA), H.R. 3580
- Federal Register, vol. 73, no. 60, March 28, 2008
- Prescription Drug User Fee Act (PDUFA) IV Drug Safety Five-Year Plan 2008-2012, December 200
- Guidance for Industry: Development and Use of Risk Minimization Action Plans, March 2005