Background Materials for REMS Standardization and Evaluation Public Meeting: REMS Tools

back to REMS Public Meeting Materials Table of Contents

3 REMS Tools

A REMS “tool” is a process or system designed to ensure that certain safe use conditions are in place so that prescribers, pharmacists (or other dispensers) and/or patients are aware of the serious risks of the drug and carry out any specific requirements needed to mitigate those risks. The Federal Register notice that announced this public meeting included a number of questions about REMS tools. To help stakeholders answer these questions, this section includes a description of each REMS tool’s important features, and provides examples of how each tool has been used.

Disclaimer: This section of the document represents FDA’s initial efforts to systematically characterize variation across REMS. This section seeks to describe REMS tools and their use in REMS programs as accurately as possible, but given the scope, scale, and diversity of REMS programs and tools, it cannot guarantee that the information contained in this document is complete and reflects the most current REMS documents and materials. Healthcare providers and patients who need information about a particular REMS program should refer to the information and materials provided by the drug manufacturer. Up-to-date information on REMS programs is also available on FDA’s approved REMS website.

The tools described in this section of the document are organized into the following categories:

	Tool Category	Description / Purpose	Example Tools
3.1	Communications to Healthcare Providers	Tools used to disseminate information to healthcare providers to help ensure they are aware of the REMS and their responsibilities within the REMS	Dear Healthcare Provider Letters, Websites, Journal Information Pieces
3.2	Training of Healthcare Providers	Tools that ensure that healthcare providers understand the drug’s risks, how to use the drug safely, and what the REMS requirements are.	Training Materials, Healthcare Provider Overviews, Prescribing Information
3.3	Enrollment and Certification of Healthcare Providers	Tools that ensure that healthcare providers meet all necessary requirements to be able to safely prescribe, dispense, and/or administer the drug.	Prescriber and Dispenser Enrollment Forms
3.4	Initiation of Therapy and Patient Counseling	Tools that ensure that patients and prescribers make informed benefit-risk decisions, that patients understand how to use the drug safely, and that appropriate screening and patient selection takes place.	Patient-Prescriber Agreements, Patient Educational Materials, Medication Guides, Counseling Tools
3.5	Ongoing Patient Care	Tools that ensure that healthcare providers and patients meet safe use conditions, are appropriately monitored, and carry out REMS requirements.	Patient Monitoring, Verification of Safe Use Conditions
3.6	Adverse Event Reporting	Tools that facilitate the reporting and collection of information on adverse events of interest.	Patient Registries, Adverse Event Reporting Forms
3.7	Distribution Controls	Tools that ensure that only certified and/or enrolled parties can obtain the drug.	Distributor enrollment Forms

3.1 Communications to Healthcare Providers

REMS communications are messages that are delivered to healthcare providers in the form of letters, articles, and other media. Communications are designed to make healthcare providers aware of the serious safety issue, the REMS requirements, and where they can go to get more detailed information. Communications are not designed to provide comprehensive information about safe use of the drug or directly support the completion of REMS requirements.

REMS communications are included in the approved REMS. In many cases, communications are issued as part of a REMS’ communication plan, which is directed towards prescribers and other healthcare providers and specifies the audience that should receive the communication, the key messages to be delivered, the frequency of the communication and the medium through which the communication will take place. Communications may also be included as part of a REMS’ ETASU.

To date, REMS have used just a few different communication tools, including letters, websites, and journal information pieces.

3.1.1 Letters

The most frequently-used form of REMS communication is the letter. Letters may be delivered directly to healthcare providers or to the healthcare providers though professional societies that represent them.
Letters to healthcare providers, often referred to as Dear Healthcare Provider Letters (DHCPs) may cover any topic related to the REMS, but are most frequently sent when a REMS is first approved to make healthcare providers aware of the existence of the REMS and the safety issue that the REMS is intended to mitigate. Other letters may be used to inform or remind healthcare providers of specific REMS requirements, new safety information, changes to the REMS, or the availability of certain REMS materials.
In addition to sending letters to individual healthcare providers, a few REMS programs send letters to professional societies that represent healthcare providers who are likely to use the drug. Like letters to individual healthcare providers, these letters are typically sent when a REMS is first approved to make the societies aware of the existence of the REMS and the safety issue that the REMS is intended to mitigate, and encourage professional societies to share this information with their members.

Key Features of Letters:

Delivery method: Letters may be delivered to healthcare providers by mail, e-mail or both. Many sponsors use their field representatives to deliver these letters along with other REMS communications and REMS materials, but the use of field representatives is not usually required as part of the REMS.
Frequency of letters: Most letters are sent when a REMS is first approved, however there have been some REMS that have required annual delivery of the letter for a period of time such as the first three years of approval of the REMS. There are also REMS letters that are sent to any new healthcare provider that decides to enroll in the REMS program.

Examples:

3.1.2 Websites

REMS usually include websites that provide general information about the REMS program, and may include online versions of REMS materials such as enrollment forms and training materials as well as downloadable print forms and materials. Websites that are part of a REMS are kept distinct from websites the sponsor may use for promotional purposes.

Examples:

3.1.3 Journal Information Pieces

Several REMS include journal information pieces to raise awareness of a drug’s risks and/or its REMS. These pieces are typically published in leading journals that target the medical specialties most likely to prescribe the drug or to treat patients who are taking the drug (e.g., prescribers who are likely to treat patients experiencing an adverse event associated with the drug). These pieces may also be shared at scientific meetings that prescribers are likely to attend.

Examples:

3.2 Training of Healthcare Providers

Currently, all REMS with ETASU include training or education for healthcare providers (e.g., prescribers and/or dispensers). REMS training provides information about the risks associated with the drug, how to use the drug safely, or the requirements of the REMS program. Training is almost always required for REMS that require healthcare provider certification (see below for more details about HCP certification)⁹.

The sponsor is usually responsible for making training available to individual healthcare providers, and often append the training materials to REMS communications. But when REMS provide training to healthcare settings, the designated healthcare setting representative typically takes responsibility for training that healthcare facility’s staff.

Most REMS training is directed towards the healthcare providers who prescribe, dispense, and administer the drug. But the training may also be required for staff within a healthcare setting who are involved in the care of the patient who is taking the drug, including those who counsel, monitor, or treat patients.

A variety of tools have been used to train healthcare providers, including REMS program overviews and training materials such as slide decks and program brochures. Training tools provide information about the risks associated with the drug, how to use the drug safely, and/or the requirements of the REMS program. In some cases, all of this information is captured in a single tool; in other cases, the training tools may be augmented with other tools that the healthcare provider can use to reinforce particular parts of the training or to reference at later time.

The REMS for extended-release/long-acting opioid analgesics makes training available to prescribers through continuing education (CE) providers. The CE providers develop the training based on an FDA Blueprint for Prescriber Education. The CE component of the REMS for the extended release/long-acting opioid analgesics is FDA’s first experience using CE as the tool for prescriber education required as part of a REMS. The lessons FDA learns with implementation will help inform future planning for REMS and CE.

Examples:

3.2.1 Training Materials

REMS training programs and/or materials are educational tools that are designed to provide healthcare providers with comprehensive training on the risks addressed by the REMS, how to mitigate those risks, and what the healthcare provider’s requirements are under the REMS. REMS programs may have one or multiple training materials. Healthcare providers are usually expected to review training materials prior to prescribing or dispensing a drug, and may be supplemented by other tools to be used in the course of clinical care.

As mentioned previously, the review of training materials is an important requirement for healthcare provider certification in many REMS. However, some REMS include healthcare provider training but do not require healthcare provider certification. In some of these REMS, the healthcare provider may be asked to fill out a training confirmation form to track which prescribers have completed the training. Prescribers of Mycophenolate and Qysmia, for example, are asked to complete forms to confirm that they have received training.

REMS training materials are based on, but distinct from, the FDA-approved prescribing information. Like prescribing information, training materials provide detailed information about the drug’s risks and how to use the drug safely; but unlike the prescribing information, the training materials tend to focus on the specific, serious risk targeted by the REMS. Training materials also provide detailed information about the operation of the REMS program that may not be found in the prescribing information.

Key Features of Training Materials:

Format: Training materials may be formatted as written guides, brochures, slide decks, or transcripts for delivery by a trainer.
Delivery: The materials may be delivered to healthcare providers in a variety of ways: print materials may be mailed or handed to a healthcare provider, training may be made available online, or training may be provided by a trainer in person or over the phone. Healthcare facilities that train their own staff are typically free to use a range of methods to deliver the training.
Knowledge Assessments: Some training materials incorporate knowledge assessment questions into the training.

Examples:

3.2.2 Prescribing Information

FDA-approved prescribing information (also known as “PI” or “labeling”) contains comprehensive information on a drug’s indications, usage, and risks, including risks that are not targeted by the REMS. The prescribing information may also include a medication guide. Healthcare providers are always encouraged to read the prescribing information in addition to participating in any other REMS training, and some REMS require prescribers to acknowledge that they read the prescribing information in order to become certified. Even though prescribing information may play an important role in the REMS, it is not usually part of a REMS’ appended materials and is not reviewed as part of the REMS.

3.2.3 Program Overviews

Program overviews are documents that help healthcare providers understand how the REMS program operates and what their responsibilities are within the program. They are generally found only in REMS that require healthcare providers to be certified. They are often designed to serve as a succinct reference tool, rather than as a source of comprehensive information.

Examples:

Entereg: Program Overview

3.2.4 Knowledge Assessments

A few REMS include post-training knowledge assessments, typically in the form of multiple-choice questions. These knowledge assessments should not be confused with the Knowledge, Attitude and Behavior (KAB) surveys that sponsors use to conduct their REMS assessments. Post-training knowledge assessments can help assess healthcare providers’ understanding of REMS training materials, reinforce key training messages, and ensure that the prescriber understands the drug’s risks and how to use the drug safely. Completion of knowledge assessments may be required in order for a healthcare provider to become certified. When knowledge assessments are included in training materials, they may take place at the end of the training, or assessment questions may be interspersed throughout the training.

Key Features of Knowledge Assessments:

Criteria for successful completion: REMS usually require prescribers to get a certain number of questions right in order to successfully complete the knowledge assessment. If a prescriber answers a question incorrectly, prescribers may be offered another opportunity to answer the question or may be presented with a different question. One REMS temporarily blocks prescribers from being able to enroll in the REMS if they are unable to successfully complete the knowledge assessment after 3 attempts.
Feedback on answers: In some cases, healthcare providers receive feedback on incorrect answers explaining why their answer was wrong and presenting additional training material relevant to that question. When healthcare providers take knowledge assessments on-line, in person, or over the phone they may receive instantaneous feedback on their answers, but feedback can take significantly longer when knowledge assessments are submitted via fax or mail.
Knowledge assessments developed by CE providers: The REMS for extended-release/long-acting opioids includes knowledge assessments that are developed and administered by the continuing education providers who provide the REMS training

Examples:

3.2.5 Other Training Tools

In addition to prescribing information, REMS overviews, and training materials, REMS may include additional training tools designed to address specific issues related to safe use of the drug.

One important type of training tool is the “enabling tool.” Certain tools such as checklists and counseling guidelines help prescribers apply their learning to practice, and support ongoing care of patients.

Examples:

3.3 Enrollment and Certification of Healthcare Providers

In most REMS with ETASU, healthcare providers must complete certain REMS requirements in order to be able to prescribe, dispense, or order a drug. Once a healthcare provider or setting has met these requirements, they are referred to as “certified.” For healthcare providers who prescribe the drug, the process for obtaining this certification is referred to as “prescriber certification,” and for healthcare providers and settings that dispense the drug, this process is referred to as “dispenser certification.”

In order to become certified, healthcare providers must meet a number of requirements. Nearly all approved REMS require that healthcare providers enroll in the REMS by providing basic demographic information to the REMS program (typically through the use of an enrollment form). Those that do require healthcare providers to enroll also require them to acknowledge that they understand the drug’s risks and how to use the drug safely and agree to follow certain REMS requirements when treating patients with the drug. In addition, REMS with prescriber certification may require that providers acknowledge or demonstrate (for example, via a knowledge assessment) that they possess certain experience or abilities (e.g., the ability to diagnose or treat certain adverse events), have completed REMS-required training, or that they have systems in place to ensure and document the completion of REMS requirements. Prescriber certification is often verified by pharmacists prior to dispensing medication to verify safe use as part of a REMS.

REMS may require the certification of an individual provider, as described above, or of an entire healthcare setting or organization. At this time, all REMS that require prescriber certification certify individual prescribers, while all REMS that require dispenser certification certify the entire dispensing setting. In order for a setting to become certified, it must designate a health care setting representative to manage that setting’s certification and enrollment in the REMS.

Key Features of Healthcare Provider Enrollment and Certification:

Setting-specific certification: In REMS that include certification of dispensing settings, the requirements that a setting must meet depends on the role that the setting plays in the distribution, dispensing, and administration of the product. For example, the REMS for Zyprexa Relprevv and Tysabri have multiple types of dispenser certification, including separate certifications for dispensers who dispense the drug but do not administer it and for settings in which the drug is administered directly to patients. In addition, certain settings may be exempted from REMS requirements. For example, the risks that the TIRF REMS seeks to address, such as accidental exposure and overdose, are more easily managed in the inpatient setting. As a result, prescribers do not need to become certified in order to prescribe TIRF products to inpatients, and some of the requirements that the REMS places on dispensers applies only to those who dispense TIRFs to outpatients.
Indication-specific certification: The safety profile of a product may vary by indication and patient population. Therefore, certain REMS certification requirements may vary. For example, even though ESAs have multiple indications, the risk addressed by the ESA REMS is specific to its use in cancer patients, and the REMS only requires certification of healthcare providers and settings that wish to prescribe or dispense ESAs to cancer patients. Similarly, certain aspects of certification for the Tysabri REMS differ depending on whether the prescriber is treating patients with Multiple Sclerosis or Crohn’s Disease.
Re-certification: REMS may require healthcare providers and settings to be re-certified or to repeat certain certification requirements, such as training or the completion of an enrollment form. Most commonly, healthcare providers and settings must re-certify at regular intervals. In REMS with periodic re-certification requirements, the sponsor is usually asked to remind healthcare providers of the need to re-certify so that they do not experience any interruption in their ability to prescribe or dispense the drug.

Examples:

3.3.1 Enrollment Forms and Prescriber Agreements

Enrollment forms are used by healthcare providers to provide basic identifying and demographic information to the REMS programs. Enrollment allows sponsors to track which healthcare providers have been certified and communicate with them. Successful enrollment in a REMS may serve as evidence that a healthcare provider has met all requirements for certification and is therefore able to prescribe or dispense the drug. For this reason, the terms “enrolled” and “certified” are often used interchangeably within REMS programs.

When filling out the enrollment form, healthcare providers are usually required to review and sign certain agreements and acknowledgments, which are included on the form. The specific content of these agreements and acknowledgments depends largely on the requirements of the specific REMS, and tend to fall into three major categories:

Acknowledgments that the healthcare provider has met certain requirements for certification.
Agreements that the healthcare provider will follow certain REMS requirements in the future.

In the forms, healthcare providers may also consent to receiving communications related to the REMS and to permit the sponsor to monitor or audit their compliance with the REMS.

All enrollment forms collect basic information about the healthcare provider and/or healthcare setting representative and their practice setting so that they can be tracked and receive communications from the REMS program. Most REMS also ask healthcare providers to submit a number that uniquely identifies them, such as a National Provider Identifier (NPI) number or, for prescribers, a State License Number. (Note: Some REMS may identify healthcare providers using DEA numbers for controlled substances).

Key Features of Enrollment Forms and Prescriber Agreements:

Link to certification: All REMS that require certification also require that prescribers complete an enrollment form, but certain REMS may not provide dispensers with an enrollment form. Instead, dispensers that wish to become certified to dispense these drugs must enter into a contractual agreement with the manufacturer of the drug.
Combined prescriber-patient enrollment: In most REMS, prescribers are asked to complete a dedicated prescriber enrollment form before they begin treating patients. The REMS for Tracleer and Tysabri, however use a single form to enroll both prescribers and patients in the REMS at the initiation of therapy. Both forms contain sections for both prescriber and patient enrollment. In the Tracleer REMS, prescribers must fill out the prescriber enrollment section of the form the first time they prescribe Tracleer to a patient. In the Tysabri REMS, the prescribers must fill out the enrollment section of the form every time they initiate treatment with a new patient.
Submission method: REMS usually ask prescribers to print, sign, and submit enrollment forms through mail or fax. A small number of REMS permit prescribers to submit their enrollment forms online and do not require a handwritten signature.

Examples:

3.4 Initiation of Therapy and Patient Counseling

At the initiation of therapy healthcare providers may:

Counsel patients on the benefits and risks of different therapies and help them determine whether a REMS drug is appropriate
Counsel and educate patients on safe use of the drug
Solicit information about a patient’s risk factors for an adverse event or, their likelihood of benefiting from the drug, to inform prescribing decisions

REMS may include educational materials and counseling tools to support each or all of these steps. After the decision to use a drug has been made, these same tools can help ensure that patients know how to use the drug safely. Tools such as patient-prescriber agreements and prescription order forms facilitate the screening of patients to ensure that they are appropriate candidates for therapy, and to document that safe use conditions have been met.

Examples:

Erythropoiesis Stimulating Agents (ESAs) including Epogen, Procrit, and Aranesp may increase the risk of shortened overall survival or tumor recurrence in cancer patients. The REMS includes counseling tools and a patient-prescriber agreement for cancer patients to ensure that patients are aware of these risks when deciding whether to use ESAs.
Before starting patients on Versacloz, a clozapine product, healthcare providers must document that the patient is appropriate (e.g., has not experienced serious adverse events with clozapine in the past) and are undergoing regular monitoring of white blood cell counts and absolute neutrophil counts. This documentation is accomplished using Versacloz’ prescription order form at the initiation of therapy.
For drugs that cause birth defects, prescribers may need to determine whether a female patient is able to get pregnant, in which case pregnancy monitoring may be needed. If that patient is already pregnant, it may not be appropriate to initiate treatment with that drug. For example, prescribers of Pomalyst, Revlimid, and Thalomid must classify the patient in one of six risk categories based on their potential to be sexually active and/or become pregnant. The REMS provides a different patient prescriber agreement and enrollment form for each risk category, and prescribers document the patient’s risk category by submitting the appropriate form.

3.4.1 Counseling Tools for Healthcare Providers

REMS may provide healthcare providers with tools to help them counsel patients. This may include materials that are directed towards the prescriber, and it may also include material that can be shared with the patient and given to the patient after the counseling session. Counseling tools are most often used at the initiation of therapy, but may also be used to facilitate follow-up counseling.

For prescribers who want to refer patients for counseling, some REMS provide tools to facilitate this process. For example, the Mycophenolate REMS offers prescribers letters that can be used to refer patients for to an obstetrician/gynecologist for contraceptive counseling, and the isotretinoin REMS provides a version of its counseling guide for use in referrals.

Examples:

3.4.2 Patient-Prescriber Agreements and Patient Enrollment Forms

Patient counseling is frequently provided at the initiation of therapy to educate patients about the REMS, and patient-prescriber agreements are used to assist in this process and document that the counseling took place. When such agreements are used, the prescriber is usually responsible for ensuring that this form is completed and signed.

Like healthcare provider enrollment forms, these documents contain agreements and acknowledgments for patients and prescribers, and the content of the agreements may vary depending on the requirements of the specific REMS. These agreements may also serve as a patient enrollment form, providing patient information to the REMS program that allows the sponsor to track patients and ensure that only those who have completed the patient-prescriber agreement can obtain the drug.

A small number of REMS use “patient agreements” in lieu of patient-prescriber agreements. While similar in structure and purpose to the patient-prescriber agreement, they do not include prescriber agreements and do not require the prescriber to sign the form. The prescriber may still be responsible for ensuring that the patient reviews and signs this form.

Key Features of Prescriber-Patient Agreements and Patient Enrollment Forms:

Documentation of agreement: Prescribers and/or healthcare settings may be asked to maintain a signed copy of the agreement in the patient’s medical record. When the patient-prescriber agreement also acts as an enrollment form, prescribers may be asked to submit the completed document to the sponsor instead of or in addition to keeping it in the medical record.
When prescribers are asked to place the completed agreement into the patient medical record, it can pose challenges for prescribers who use electronic health records, particularly in health systems that require forms to adopt a standardized format. Some programs allow prescribers to place an electronic scanned copy of the agreement into the record. The REMS for Epogen/Procrit and Aranesp allow healthcare settings to modify the enrollment form as needed to permit integration into electronic health records.
Prescription Order Forms: Some patient-prescriber agreements also act as prescription order forms that allow prescribers to order a new prescription.
Medical history and screening: Patient-prescriber agreements may also include questions about the patient’s medical history to assist in the screening of appropriate patients and track how the drug is being used. This is discussed in greater detail in the “Documenting Safe Use Conditions” section of this document.

Examples:

3.4.3 Medication Guides and other Patient Educational Materials

Medication Guides are the most frequently-used patient educational materials in REMS. Medication guides generally are considered part of the REMS but are reviewed separately as part of the drug’s prescribing information. Unlike other patient educational materials, the medication guide includes information on the drug’s major risks – not just the risks that are being addressed by the REMS.

The use of medication guides predates REMS, and medication guides are used outside of REMS. Medication guides must be dispensed with the drug and in addition, when part of a REMS, with ETASU, prescribers will be instructed to use the medication guide as a counseling tool, to give the medication guide to patients when the drug is first prescribed, and, in some cases, to continue providing the medication guide on subsequent office visits.

Several REMS with ETASU use other patient educational materials to supplement the medication guide by discussing specific risks in greater detail.

Although it is not considered an educational material, the patient agreements found in certain REMS highlight key information that the patients need to know, and may help to reinforce other REMS educational material.

Key Features of Patient Educational Materials:

Format: Among REMS with ETASU, nearly all patient educational materials are printed, written materials. One exception is the educational DVDs that are included in the iPLEDGE program.
Delivery method: All medication guides are provided to patients by the dispenser of the drug, and, in REMS with ETASU, medication guides are often provided by the prescriber as well. Most other REMS educational materials are provided to the patient by the prescriber.
Length: Patient educational materials vary in length. Currently, REMS medication guides may range from 1 to 8 pages. The ER/LA Opioid REMS counseling document is only one page, while other patient booklets and brochures may be 10 pages or longer.
Contraception Information: All REMS for drugs that carry the risk of birth defects include guidelines on how to avoid becoming pregnant and include an overview of contraceptive options, but the format and content of the guidelines varies across REMS. (variations in FDA’s approach to management of teratogenic risk addressed at an advisory committee meeting in December 2012)
Comprehension Questions: REMS may include questions to confirm a patient’s comprehension of key REMS messages.

Examples:

3.4.4 Prescription Order Forms

Certain REMS include prescription order forms. These forms are used to order product from a pharmacy and, while doing so, may remind prescribers of counseling, screening, and dosing requirements. Prescription order forms may be included as part of patient-prescriber agreements, allowing the dispensing pharmacy to easily verify that the agreement was completed when they receive the prescription.

Key Features of Prescription Order Forms:

Frequency of use: Some prescription order forms are used only at the initiation of therapy, while others are used each time a patient needs a new prescription.
Custom forms for the Department of Veterans Affairs (VA): REMS include special prescription order forms to accommodate the requirements of the Department of Veterans Affairs. Patients who obtain treatment in the Department of Veterans Affairs need to submit their prescription to a specialty VA pharmacy and include VA-specific information on the prescription. Other government and integrated healthcare systems may need similar accommodations.
Documentation of safe use conditions: Prescription order forms may allow prescribers to document and verify that safe use conditions are in place at the time of prescribing.

Examples:

3.5 Ongoing Patient Care

Once the patient has been initiated on therapy, REMS may require ongoing monitoring to watch for adverse events and ensure that the patient remains an appropriate candidate for treatment. During this phase, healthcare providers may be required to:

Continue counseling patients and remind patients of safety messages
Continue to monitor for contraindications and adverse events
Periodically re-assess the benefits and risks of the treatment to ensure that the therapy remains appropriate

During this phase, additional counseling may be provided by the healthcare provider to reinforce any prior patient education and counseling. In addition, patients may receive additional copies of educational materials from the pharmacist or at subsequent office visits from the prescriber. Many REMS require routine monitoring to ensure that safe use conditions are in place, and REMS may include special tools and forms to ensure that this is happening, including documentation of safe use conditions by prescribers and dispensers, and verification of safe use conditions prior to dispensing.

Patient Comprehension Questions: The REMS for Revlimid, Thalomid, Pomalyst, and Isotretinoin, include monthly patient comprehension questions to ensure that patients continue to understand the need to use contraception, as all four of these drugs can cause serious birth defects if a patient becomes pregnant before, during, or immediately after treatment.

3.5.1 Verification of Benefit and Treatment Maintenance Forms

Certain REMS drugs carry serious risks that are difficult to predict or prevent, and may cause irreversible harm to the patient. In these cases, it is important for patients and prescribers to regularly assess the benefit of the drug to ensure that it continues to justify the ongoing risk. Certain REMS include special treatment maintenance forms that prescribers and patients must complete to verify that the patient continues to benefit from the drug and has not experienced any adverse effects.

Examples:

3.5.2 Patient Monitoring and Monitoring Forms

A number of REMS require regular monitoring of patients, such as laboratory tests and periodic assessments by healthcare providers. In some cases, the monitoring may be documented using special monitoring forms. In other REMS, prescribers record the results of the monitoring and share the findings with the sponsor over the phone or using a website. Other REMS require that pharmacists confirm with the prescriber that monitoring has taken place before dispensing the drug.

Key Features of Patient Monitoring and Monitoring Forms:

Frequency of Monitoring: The frequency of the required REMS monitoring depends on a number of factors, including the purpose of the monitoring and the consequences of failing to monitor frequently.
Timing of monitoring: Monitoring may occur at a range of times during the medication use process, depending on who is doing the monitoring (e.g., the prescriber, the dispenser, etc.), when adverse events are most likely to occur (e.g., immediately after administration of the drug) and when the information from monitoring is most likely to be useful (e.g., before a drug is dispensed to help determine whether therapy needs to be stopped).

Examples:

3.5.3 Verification of Safe Use Conditions

In REMS, dispensers are frequently called upon to verify that safe use conditions are in place before dispensing the drug. For example, a dispenser may be asked to verify that the prescriber of the drug is enrolled and trained, that the patient has been enrolled and/or counseled, and that any necessary screening or monitoring have been completed

The methods used to verify that safe use conditions are in place may depend in part on the setting in which the drug is typically used. When drugs are prescribed and dispensed in the same setting, the setting may be responsible for setting up a system to ensure that the drug is only dispensed when certain safe use conditions are in place.

When drugs are prescribed and dispensed in separate settings, a more standardized process is usually put in place to ensure that dispensers are able to verify safe use conditions that may have been carried out by a number of different healthcare providers. In some cases, the sponsor may take responsibility for tracking whether safe use conditions have been met: The healthcare providers who are responsible for carrying out safe use conditions report doing so to the sponsor, and those who dispense the drug are required to obtain “dispensing authorization” from the sponsor before dispensing the drug.

Key Features of Verification of Safe Use Conditions:

Authorization Numbers: In many REMS, prescribers who complete REMS requirements for a particular prescription will receive an “authorization number” from the prescriber. By submitting that authorization number to the dispenser, they document that safe use conditions have been met. The dispenser then verifies with the sponsor that the authorization number is valid before dispensing the drug.
Prescription Order Forms: Some REMS ask dispensers to fill prescriptions only after verifying they have been entered into a prescription order form, monitoring form, or other documentation of patient monitoring.
Electronic Verification of Safe Use Conditions: More recently, REMS have begun to conduct dispensing authorizations in retail pharmacies using existing pharmacy management systems, the computer systems that retail pharmacists use in their day-to-day practice. These systems use the existing systems used to process third party prescription claims in order to automatically verify safe use conditions. They may also allow for the inclusion of “hard stops” in the pharmacy system to prevent unauthorized dispensing.

Examples:

In iPLEDGE, pharmacists must go to the iPLEDGE website and obtain a special “Risk Management Authorization” number, which confirms that the prescriber is certified and that the patient has answered contraception questions and received a negative pregnancy test.
In the Lotronex REMS, certified prescribers are asked to place a sticker on all Lotronex prescriptions, and pharmacists are then asked to check for these stickers on the prescription to make sure that the drug was prescribed by a certified prescriber. At a July 10, 2013 meeting of the Drug Safety and Risk Management Advisory Committee, the committee voted in favor of replacing this program, expressing concerns that it was incompatible with electronic prescriptions and was not integrated into pharmacists’ typical workflow.
In the TIRF REMS, retail pharmacies’ pharmacy systems automatically check with a sponsor database before being permitted to dispense.
Dispensers of Juxtapid and Kynamro may only dispense new prescriptions after receiving a “Prescription Authorization Form”.

3.5.4 Tools for Managing Care Transitions

Most REMS focus on the healthcare providers who typically prescribe, dispense, and administer the drug. However, patients may be treated by a range of other healthcare providers, many of whom may have a role to play in mitigating the risk of a drug.

One transition of concern is the movement of patients into inpatient facilities, which can occur at any time while the drug is being used. REMS have introduced tools and approaches to address risks during this transition. For example, Soliris and Extraneal’s REMS include special tools for patients to use to inform their care providers of these risks and how to address them. Soliris includes a patient safety card with information for hospital staff on the risk of infection in Soliris patients, and Extraneal includes a patient kit with letters and reminders to ensure that hospital staff are aware of the potential for falsely elevated blood glucose readings in Extraneal patients.

Examples:

3.6 Adverse Event Reporting

REMS may seek to collect information on adverse events to support their risk mitigation effort and facilitate the assessment and improvement of the REMS. When healthcare providers enroll in the REMS, they will often agree to report any incidents of adverse events to the sponsor. Some REMS provide adverse event reporting forms and procedures to help collect detailed information on adverse events of interest and the circumstances surrounding them. In some cases, these forms and procedures are associated with a patient registry.

3.6.1 Patient Registries for Adverse Event Reporting

As part of a REMS, patient registries may record adverse events. Patient registries are most frequently found in REMS for drugs that cause birth defects. For these products, a registry may be used to track patients who become pregnant and the outcome of the pregnancy.

Examples:

Thalomid: Pregnancy Exposure Registry Protocol

3.6.2 Adverse Event Reporting Forms

As part of a REMS program, adverse event reporting forms may be used to collect information on specific adverse events of interest. Use of these forms allows the sponsor to collect more detailed information on a greater number of cases than might be obtained through spontaneous adverse event reporting.

Examples:

3.7 Distribution Controls

In order to ensure that only certified healthcare providers who dispense REMS drugs receive the drugs to dispense, REMS programs often take steps to control the distribution of the drug. Some REMS limit distribution of the drug by requiring distributors to enroll in the REMS or sign a contract with the manufacturer assuring they will ship only to certified parties.

3.7.1 Distributor Enrollment Forms

When REMS drugs are distributed through normal distribution channels to retail pharmacies, the REMS may require distributors to enroll in the REMS using an enrollment form. The process for distributor enrollment is similar to that for other REMS stakeholders: As part of the enrollment process, distributors are required to provide basic information about their facilities, and sign a series of acknowledgments and agreements, including an agreement to ship product only to certified parties.

Examples:

Next section: 4 REMS Evaluation

References:

9. . . . with the exception of the REMS for Isotretinoin, Mifeprex, Pomalyst, Revlimid, Thalomid, Tikosyn, Versacloz. (Note that in the Tikosyn REMS, prescribers are asked to review certain training materials before prescribing, even though this requirement is not in the REMS document).

Disclaimer: This section of the document represents FDA’s initial efforts to systematically characterize variation across REMS. This section seeks to describe REMS tools and their use in REMS programs as accurately as possible, but given the scope, scale, and diversity of REMS programs and tools, it cannot guarantee that the information contained in this document is complete and reflects the most current REMS documents and materials. Healthcare providers and patients who need information about a particular REMS program should refer to the information and materials provided by the drug manufacturer. Up-to-date information on REMS programs is also available on FDA’s approved REMS website.