A. Prescriber-Directed REMS Tools
Transcript of A. Prescriber-Directed REMS Tools
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Amgen Comments: Standardizing and Evaluating Risk Evaluation and Mitigation Strategies Docket: FDA-2013-N-0502
Specific comments
A. Prescriber-Directed REMS Tools
REMS programs use a number of tools to educate prescribers and/or ensure that they carry out REMS
requirements, including screening, monitoring, and counseling patients. These tools have included risk
communications to prescribers, prescriber training, and instruments to help prescribers prescribe the
drug safely—for example, counseling guides and checklists.
1. Many REMS with elements to assure safe use provide for prescriber training on the risks of the
drug and how to use the drug safely. In some REMS, the completion of this training is required
before a person can become a certified prescriber of the drug. Sponsors provide REMS training
in a variety of formats, including in-person, online, and through printed materials.FDA is
interested in input on which formats and training approaches are most effective for prescriber
training; how frequently prescribers should be asked to take REMS training and whether a single
training is sufficient; what additional tools could be used to reinforce what prescribers learn
during the training and help them apply what they have learned; and how REMS training could
be incorporated into continuing medical education programs.
In order to be most effective, REMS Program training should be based on the principles of accuracy,
simplicity and accessibility. The format of training methods available to health care providers (HCPs)
and institutions should allow them to choose the most expedient way to complete the training.
Providing HCPs and institutions with this flexibility in training formats and approaches will allow them to
fulfill program requirements while minimizing administrative burdens, thereby enabling them to focus
on providing care to patients.
The frequency of training should be driven by the need to deliver to HCPs and institutions new or
additional information on a drug; training should not be triggered by a calendar-based schedule.
Currently, much of the training focuses on reiterating information that is already contained in the
product label, rather than on providing any additional information. As such, this training places
additional administrative burdens on providers, with little evidence of improving patient care.
In some instances, it may be useful to provide HCPs and/or institutions with periodic reminders of key safety aspects of a drug. Such reminders may be delivered more effectively and efficiently using tools and approaches other than requiring the providers/institutions to repeat REMS training. For example, the administrative burden could be decreased and the effectiveness increased by incorporating REMS training into Continuing Medical Education, continuing professional development, or other accredited health care professional training. Research studies have documented the value of CME in imparting knowledge: the scientific literature provides evidence that CME is effective in the acquisition and retention of knowledge, as well as influencing behaviors and clinical outcomes.
To maximize the effectiveness and efficiency of delivering this content through CME, it may be beneficial to design training materials that cover multiple products with similar safety concerns within a single CME program. The FDA may find it advantageous to work directly with the producers of the CME
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Specific comments
programs to tailor the course content and select the educational tool/vehicle that is most effective at engaging the specific audience and achieving the desired outcome. It also may be useful to include incentives, such as training credits, to encourage participation of HCPs/institutions in such CME or other accredited health care professional training.
2. Prescriber training often includes knowledge assessments that prescribers must successfully
complete as part of the training. These knowledge assessments, which typically take the form of
multiple-choice questions, are designed to ensure that the prescriber understands the training
material; they also serve to reinforce key messages from the training. (Knowledge assessments
should not be confused with the surveys of knowledge that drug manufacturers may conduct as
part of their REMS assessments.)FDA is interested in input on when knowledge assessments
should be included in REMS and whether they should be included in all REMS that include
prescriber training. In addition, FDA requests input on how knowledge assessments can be
designed to ensure accurate measurement of prescribers’ knowledge and how knowledge
assessments can be designed to measure or predict prescribers’ ability to apply what they have
learned in their practice.
The effectiveness of knowledge assessments is limited by several factors. First, such assessments
conducted after training evaluate only whether the HCP can recall information provided in the training;
the assessments do not indicate whether the HCP comprehends the content or can apply it correctly in
clinical practice, both arguably more likely to have a positive effect on patient safety than would mere
recall of training content. Second, no criteria have been established for identifying what constitutes
success in a REMS program. Success should not reflect solely whether an HCP remembers the risk
associated with a product, but rather whether he/she applied that knowledge in clinical practice, leading
to an improvement in patient safety. Thus, there may be little or no correlation between “high scores”
on the assessments and success in a REMS program. Third, the use of knowledge assessments will not
predict accurately risk mitigation in situations in which HCPs are skeptical of the causal association
between a drug and its potential risks, as reflected in the product label, and thus deliberately choose not
to modify their behavior. In these instances, knowledge assessments, training, and retraining likely will
not result in the HCPs incorporating the risk information into their practice and will not lead to improved
patient outcomes. Fourth, training and knowledge assessments focus on providing information on the
nature of the risks, not necessarily on how to mitigate those risks. Consequently, HCPs are not provided
with practical information they can incorporate into their clinical practice, regardless of the number of
assessments, training and retraining employed. In order to contribute measurably to improved patient
safety, HCPs must be provided with information on how the information can be applied to their practice
to mitigate risk. For example for drugs with a risk of teratogenicity, HCPs can be advised to take such
steps as administering pregnancy tests and counseling patients to take contraceptives.
Given the inherent limitations in the use of assessments as a measure of the effective of a REMS
program, we recommend the following criteria as necessary for a REMS program to be deemed
successful:
There is a clearly identified risk to be mitigated
There is a well-defined risk mitigation goal that is based on improved public health
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Specific comments
The goal is linked to achieving a desired behavior and is monitored by a measurable metric
It should be acknowledged that in some instances, risks cannot be eliminated or mitigated. In those
cases, perhaps another risk management approach would be more appropriate in lieu of REMS.
Furthermore, it should be considered that it is often difficult to distinguish the effect of a specific REMS
program from the effect of other risk management efforts or activities. Therefore, it is recommended
that a more comprehensive evaluation of the overall risk mitigation efforts for a product be conducted
through existing pharmacovigilance activities, e.g., patient/physician registries or database studies.
In summary, given that it is unclear whether knowledge assessments are effective tools for measuring or
ensuring understanding of educational materials, assessments should be used judiciously, rather than
being applied as a core component of all REMS programs. For example, they may be applied in
instances in which a deficiency in HCP knowledge has been identified and a determination has been
made that a knowledge assessment will be an effective step in rectifying the knowledge gap and
achieving the desired behavior. In addition to being used judiciously, they should be streamlined to
minimize the burden on HCPs. Finally, as noted above, knowledge assessments should not be used as
the basis for assessing the performance of a REMS program.
3. Once prescribers have met all requirements for certification under the REMS (e.g., completed
training), they generally must complete an enrollment form to be recognized as certified and
able to prescribe the drug. Generally, by completing, signing, and submitting the enrollment
form, prescribers acknowledge their understanding of the drug’s risks and the REMS
requirements. In some REMS, the enrollment form also is used to share information about the
risks of the drug and how to use the drug safely. FDA is interested in stakeholder input on
whether the information and agreements included in current REMS prescriber enrollment forms
are presented in a way that is easy for prescribers to understand. Also, what, if anything, should
be done to standardize, simplify, or streamline prescriber enrolment forms and the overall
prescriber enrollment process?
To increase the efficiency and reduce the administrative burden of prescriber enrollment, REMS
programs can be incorporated into existing workflows of providers, e.g., in electronic health records,
electronic prescribing platforms or claims adjudication processes.
While the process of prescriber enrollment can and should be streamlined (where such enrollment is
deemed necessary to effectively manage a risk), it may be difficult to standardize the content of the
enrollment forms, since much of the content is specific to the risk of the product and the US Package
Insert. However, some standardization may be possible, e.g., the overall format for the form could be
standardized, with the content of certain sections customized for product-specific risks.
4. What else can be done to improve the effectiveness of existing prescriber-directed REMS tools,
to standardize them, to reduce their burden, and/or to better integrate them into the health
care delivery system?
Improvements in existing prescriber-directed REMS tools can be achieved by instituting a consolidated,
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Specific comments
universal REMS platform. This platform could include an HCP web-based portal that facilitates and
tracks enrollment, training, certification and surveys. The platform also could serve as an information
hub that provides HCPs and institutions with ready access to risk disclosure and other important
information. Clinics could use the web-based portal while they are implementing the real-time interface
to integrate with their individual electronic medical record (EMR) systems. More details on this
platform are provided in response to Section D.2.
5. What tools and technologies not currently used in REMS could be incorporated into REMS to
help educate prescribers and ensure that they carry out REMS requirements? What evidence
exists to support the effectiveness of these tools and technologies?
A consolidated, universal REMS platform, as described in A.4 and D.4, would facilitate educating
prescribers and tracking their completion of REMS-related activities.
6. What projects could be carried out to standardize the provision of prescriber education in
REMS?
7. What projects could be carried out to better integrate REMS into prescriber practice settings?
A useful project would be to pilot a universal REMS web-based platform, as described in response to
A.4. This platform could integrate such REMS activities as documenting HCP training completion, as well
as completion of acknowledgement and enrollment forms. The platform also could incorporate into
existing or emerging EMR systems any alerts and reminders pertaining to a specific drug.
8. What methodologies exist or might be developed to assess the effectiveness of prescriber-
directed REMS tools, the tools’ burden on the health care delivery system, and the effect of
these tools on patient access?
One approach to assessing the burden that prescriber-directed tools impose on the health care delivery system would be to convene a working group of thought leaders throughout the health care system to identify the burdens and patient-access issues associated with REMS tools. The National Comprehensive Cancer Network undertook a similar approach, gathering information from experts from NCCN Member Institutions. Based on its work, NCCN published a published a white paper in 2010, identifying numerous challenges, including increased provider burden and incorporation of REMS into clinical practice.1
B. Patient-Directed REMS Tools
REMS programs may use a number of tools to educate and counsel patients, provide patients with
information about the risks of the drug, and help to ensure that patients use the drug safely. These tools
may include patient enrollment in the REMS, patient monitoring, counseling by health care
professionals, Medication Guides, and other patient-directed educational materials.
1 Johnson PE, Dahlman G, Eng K, Garg R, Gottlieb S, Hoffman JM, Howell P, Jahanzeb M, Johnson S, Mackler E, Rubino M,
Sarokhan B, Marc Stewart F, Tyler T, Vose JM, Weinstein S, Li EC, Demartino J. NCCN Oncology Risk Evaluation and Mitigation Strategies White Paper: Recommendations for Stakeholders, J Natl Compr Canc Netw. 2010 Sep; 8 Suppl 7:S7-S27.
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1. REMS use a range of written materials to help educate and counsel patients, including
Medication Guides. In some cases, health care practitioners give these materials to patients to
read on their own, and in other cases health care providers are asked to review these materials
with patients and use them in patient counseling.
REMS materials designed to educate and counsel patients can be useful tools as the basis for discussions
between HCPs and their patients. In some instances, standardization of these tools could help reduce
providers’ administrative burden. However, these materials should be sufficiently flexible to allow HCPs
to tailor their use to a specific patient, and they should not interfere with the delivery of health care.
Standardization of materials such as MedGuides would be a useful endeavor. MedGuides vary in length and level of detail across different products, with more lengthy MedGuides having the potential to create confusion and information-fatigue for patients. In fact, FDA itself expressed concern about the impact of length and level of detail in MedGuides, noting that “lengthy information could result in unnecessary or even dangerous barriers to the effective communication of important concepts.”2 To remedy this situation, it would be advisable to provide patients with concise and easy to comprehend safety and benefit information on a medicine, and to emphasize the information that is particularly important. Research has suggested that the volume of information, as well as the manner in which it is presented, can have a measurable impact on patients’ ability to make good decisions with respect to health information. For example, in a study exploring the presentation of information on the comparative performance of hospitals, researchers found that consumers evidenced better comprehension and improved decision-making when provided with less information and when that information was presented in formats that “ease the cognitive burden and highlight the meaning of important information,” relative to situations in which the consumers were supplied with more information, presented in less accessible formats.3 In this vein, it may be advisable to explore whether for some medicines it is possible to combine the information contained in a MedGuide with that contained in a USPI, thereby reducing the number of materials providing similar and sometimes duplicative information.
Furthermore, to enable patients to make informed choices regarding treatment, it is imperative that the
information provided to them be balanced, i.e., presenting the benefits of the medicine, in addition to
presenting information on the safety risks. Furthermore, the safety risks of the drug should be discussed
vis-à-vis the risks posed by the underlying medical condition, if left untreated. In addition, patients
should be informed of how to avoid/minimize the potential risks of the drug, in instances where risk
elimination or mitigation is possible.
Ensuring that patients are not “over-warned” regarding a medicine’s risks is an important consideration
2 Federal Register: Prescription Drug Product Labeling; Medication Guide Requirements; Final Rule. December 1, 1998 (Volume
63, Number 230). Available at http://www.gpo.gov/fdsys/pkg/FR-1998-12-01/pdf/98-31627.pdf 3 Peters, E, Dieckmann N, Dixon A, Hibbard JH, Mertz CK. Less Is More in Presenting Quality Information to Consumers, Med
Care Res Rev 2007 64: 169
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Specific comments
when attempting to improve patient outcomes. Non-adherence to medication regimens continues to
be a major problem,4,5 estimated to cost the U.S. health care system between $100 billion and $289
billion annually.5,6,7,8,9,10 Non-adherence may be exacerbated when the communication materials
provided to a patient place a major emphasis on the risks of the medicine, without discussing its
benefits or placing the risks in the context of the risks of the untreated medical condition. This “over-
warning” is particularly a concern for silent diseases, such as hypertension, where a patient may not feel
ill and therefore feel less compelled to take a prescribed therapy. Any patient communication materials
that emphasize the risks o f the medicine without discussing the benefits will further dissuade the
patient from taking the needed medicine. Currently, most REMS use MedGuides and enrollment forms
as communication tools for patients. Neither of these communication materials provides a balanced
perspective on a medicine. Rather, they focus exclusively on the safety risks of the product, without
counterbalancing information on the benefits of the drug. As a result, these unbalanced materials may
inadvertently undermine efforts to improve patient outcomes.
Finally, in addition to providing more balanced information, patient communication tools could be
improved by prompting the prescriber to discuss how the potential risks of a medicine can be eliminated
or mitigated, where such a possibility exists.
2. In REMS that include patient education, what would make written educational materials more
effective? What other materials, tools, and technologies, (e.g., reference materials, checklists,
smartphone applications) might be used to help educate patients and reinforce what they have
learned?
As noted in the response to B.1, written materials aimed at educating patients would be more effective
if they included balanced information that discussed the risks of the medicine in the context of its
benefits, as well the risks associated with not treating the underlying medical condition.
3. How could the provision of information to patients be standardized, and what are the most
efficient ways of providing information to patients given the variety of patient information
needs and learning styles?
Given diverse patient populations, varying levels of literacy and numeracy, and the range of clinical care
settings, it may be difficult to develop standardized information that would serve all populations and
4 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005; 353:487-97.
5 World Health Organization. Noncommunicable Diseases and Mental Health: Progress Report 2002-2003. Geneva: World
Health Organization; 2003. 6 Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to improve medication adherence. Am J Health Syst
Pharm. 2003; 60:657-65. 7 Mahoney JJ, Ansell BJ, Fleming WK, Butterworth SW. The unhidden cost of noncompliance. J Manag Care Pharm. 2008; 14:S1-
S29. 8 New England Healthcare Institute. Thinking Outside the Pillbox: A System-wide Approach to Improving Patient Medication
Adherence for Chronic Disease. Cambridge, MA: New England Healthcare Institute; 2009. 9 Showalter A. Costs of Patient Noncompliance. Crystal Lake, IL: AlignMap; 2006; 1-4.
10 Task Force for Compliance. Noncompliance with Medications: An Economic Tragedy with Important Implications for Health
Care Reform. Washington, DC: Task Force for Compliance; 1994.
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Specific comments
environments. A more fruitful approach might entail working with sponsors and thought leaders in
health care communications to develop a variety of simple, concise and effective tools from which an
HCP can choose, based on the characteristics of a specific patient. Given the increasing pressures on
HCPs’ time, having a range of tools from which to choose will facilitate the physician-patient dialogue on
the benefit-risk profile of a medicine. For example, it may be useful to provide physicians with a high-
level summary of the risks and benefits of a drug, but allow the prescribers to determine the best
method (e.g., paper-based materials, web-based interactive tools, etc.) for delivering this information to
a specific patient. It also may be useful to utilize health care system stakeholders other than physicians
to conduct the benefit-risk dialogue with patients since, relative to physicians, these other stakeholders
may have more time to discuss this information with patients and answer their questions.
In the area of documentation, there may be opportunities to standardize the process and forms used for
confirming that the benefit-risk discussion was conducted, as well as to standardize forms capturing
patient acknowledgement of the risks of the treatment.
4. In many REMS, patients receive counseling that may include a discussion of the benefits and
risks of the drug as well as instructions on how to use the drug safely. In the majority of such
REMS, prescribers are called upon to counsel patients, but other health care practitioners,
including pharmacists and nurses, may also play a role in counseling patients. What are ways to
improve current REMS approach to counseling patients? How should the timing and frequency
of patient counseling be determined? Under what circumstances is it appropriate for prescribers
to provide patient counseling in a REMS, when should other providers play a role in counseling
patients in a REMS, and how can patient counseling in REMS be integrated into pharmacists’
existing medication therapy management practices?
In considering the counseling of patients, it is imperative that the information be balanced, i.e., the
patient understands clearly both the benefits and the risks of any drug before beginning treatment,
regardless of who actually delivers the message. Focus and attention should be placed on having clear
and concise materials for patients, in addition to assuring that a discussion of the benefit-risk profile of
the drug, preferably led by a health care professional, actually occurred. By allowing the prescriber to
delegate the conduct of these discussions to qualified, trained office personnel, the prescribers’
administrative burden may be alleviated and the patient may benefit from a more extensive discussion
with office personnel who, relative to physicians, may have more time to devote to patients’ questions.
The frequency of the counseling may depend on the complexity of the drug’s benefit-risk profile, as well
as the characteristics of the patient, and may be considered on a case-by-case basis. However, to
streamline the process and avoid mandatory re-education, health care providers can ask patients
probing questions that test their knowledge, e.g., what are the risks associated with the use of drug X
and what constitutes appropriate use of the drug. Accurate answers to such questions could be
prerequisites for signing new acknowledgement forms for drug administration. This information could
be captured by the HCP in the patient’s medical record, whether paper or electronic.
5. Many REMS with elements to assure safe use include prescriber-patient agreements. These
agreements are used to document that an informed discussion of the drug’s benefits and risks
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Specific comments
took place and that the patient understood the risks. Prescriber-patient agreements may also
support patient counseling by providing information for prescribers to review with patients.
Some REMS require that these agreements be signed by the prescriber and patient and
submitted to the drug manufacturer. Are the information and agreements included in
prescriber-patient agreements presented in a way that is easy for patients to understand and
act upon? What, if anything, should be done to standardize, simplify, or streamline prescriber-
patient agreement forms and the overall agreement process?
Most of the prescriber-patient agreements contain information that reiterates information contained in
the USPI or Med Guide. As such, these agreements do not appear to add value in enhancing patient
counseling by presenting new information or presenting the information in more understandable
language.
6. What else can be done to improve the effectiveness of existing patient-directed tools, to
standardize them, to reduce their burden, and/or to better integrate them into the existing and
evolving health care delivery system?
Existing patient-directed tools can be made more effective, more standardized, less burdensome and
more integrated into the existing and evolving health care delivery system thorough the development of
a patient portal, which would be part of a consolidated universal REMS platform (as discussed in D.7).
The patient portal will enable facilitation of completion and tracking of enrollments, attestations and
surveys. In addition, it can provide an information hub that serves as a ‘one-stop shop’ for content such
as risk disclosure and other supporting information. As an easy to access, web-based portal, patients
could utilize the portal in a health care setting or in another location of their choosing.
7. What tools and technologies not currently used in REMS could be incorporated into REMS to
help counsel patients, to provide them with information on the risks of the drug, and to ensure
that they use the drug safely? What evidence exists to support the effectiveness of these tools
and technologies?
As noted in B.6, a patient portal would be helpful in counseling patients. The portal could contain
interactive tools that engage the patient and educate them on a medicine’s benefits and risks. It also
could provide information on the risks of a patient’s underlying medical condition, so that the patient
understands the natural progression and consequences of the condition if left untreated.
8. What projects could be carried out to standardize the provision of benefit-risk information to
patients?
9. What methodologies exist or might be developed to assess the effectiveness of patient-directed
REMS tools, the tools’ burden on the health care delivery system, and the effect of these tools
on patient access?
C. REMS Tools in Drug Dispensing Settings
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Specific comments
Drug dispensing settings, such as prescribers’ offices, hospitals, pharmacies (e.g., specialty, retail, and
mail-order), integrated health care delivery systems, and infusion centers, often play a significant role in
REMS. This is a challenging area to address because of the wide range of health care settings involved
and because dispensers are frequently called upon to coordinate care across a range of health care
settings and practitioners and to reinforce the tools that have been used by other health care
practitioners. Specific dispensing settings may be required to obtain certification under a REMS, and, like
prescribers, the health care practitioners who dispense a drug (authorized dispensers) may be required
to complete training, counsel patients, and provide patients with educational materials, including
Medication Guides. In addition, dispensers may be required to document that certain safe-use
conditions are met before dispensing (e.g., by ordering/checking lab tests or completing a form or
checklist).
Many REMS with elements to assure safe use require that specific health care settings be certified to be
able to dispense the drug. To certify the health care setting, REMS typically require a representative of
that health care setting to agree that the health care setting will meet all REMS requirements, including
the completion of any necessary training.
1. Under what circumstances should individual practitioners within a health care setting (e.g.,
pharmacists, as opposed to pharmacies) be certified, instead of the health care setting? How
could this effectively be accomplished while minimizing the burden on the health care system?
One consideration in determining whether individual practitioners or entire health care settings should
be certified is the potential impact on patient access to medicines. If health care settings as a whole are
certified then a single non-compliant practitioner could render the entire health care setting as non-
compliant, impeding access to medicines, even for patients who did not interact with the non-compliant
practitioner. Patient access would be a particularly serious concern in instances of very large health care
settings that employ a large number of practitioners and serve a large number of patients, as well as
settings that treat patients for life-threatening conditions, where any treatment delays could have
significant ramifications.
Given the lack of solid evidence that certification manages risks or improves patient care, we
recommend eliminating the certification requirement.
2. In most REMS that include dispenser certification, each dispensing site is certified individually.
Under what circumstances would it be appropriate to use a single certification for a health care
setting with multiple dispensing sites such as a pharmacy chain, an integrated health care
system, or a hospital system?
3. In what ways can the implementation of REMS tools in different dispensing settings be
standardized, and under what circumstances might the implementation approach need to vary
to accommodate the different types of dispensing settings that can be part of a REMS?
4. What obstacles have made it difficult for authorized dispensers to obtain drugs under existing
REMS, and how can these be overcome?
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5. How can REMS be made more compatible with existing systems for the procurement and
distribution of drugs? How can REMS be integrated into any future electronic track and trace
systems?
As part of a consolidated, universal REMS platform (discussed in D.2), we encourage the development of
a distribution portal with real-time integration for distributors and wholesalers. This solution would
simplify the authorization of purchases for those products with a controlled distribution ETASU. With
enrollment, certification and training all offered via the REMS platform, authorization for purchase
would be easy to attain. Distribution and wholesalers could utilize the web-based portal while they are
implementing the real-time interface to integrate with their individual purchasing systems.
6. What else can be done to improve the effectiveness of existing REMS tools in drug dispensing
settings, to standardize them, to reduce their burden, and/or to better integrate them into the
existing and evolving health care delivery system?
7. What tools and technologies not currently used in REMS could be incorporated into REMS to
help train and certify authorized dispensers, ensure that only certified dispensers can obtain the
drug, and ensure that any safe-use conditions are met before a drug is dispensed? What
evidence exists to support the effectiveness of these tools and technologies?
Similar to the concept presented in C.5, a dedicated portal for prescribers could be included in the
consolidated, universal REMS platform.
8. What projects could be carried out to integrate REMS tools into pharmacy systems?
9. What projects could be carried out to integrate REMS tools into other drug dispensing settings,
such as hospitals, pharmacies, long-term care facilities, and integrated health care delivery
systems?
10. What methodologies exist or might be developed to assess the effectiveness of REMS tools
across the range of dispensing settings, the tools’ burden on the health care delivery system,
and the effect of these tools on patient access?
D. Approaches to Standardizing REMS Tools
Many stakeholders have asked FDA to standardize specific REMS tools like stakeholder enrollments,
Web sites, and educational materials. Standardizing REMS tools will require ongoing collaboration
among FDA, drug manufacturers, stakeholders, scientific experts, and others. To ensure that
standardized tools are effective and minimally burdensome, they should be developed in an open and
inclusive process that incorporates the feedback of all relevant stakeholders as well as the latest science
and best practices from across the health care system. To ensure the continued success of these tools,
they must be updated regularly as best practices evolve.
1. What opportunities and barriers exist for the development and implementation of standardized
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REMS tools? What are some ways that FDA can collaborate with third parties such as standards
development organizations, industry groups, professional societies, and accreditation
organizations to develop standardized REMS tools and ensure their adoption?
2. How might health information technologies such as electronic health records, pharmacy
management systems and electronic prescribing systems be used to integrate REMS into
existing health care settings? What role might health information technologies play in REMS in
the future? How can these technologies be used to inform practitioners and patients about
REMS, monitor patients, and document that any safe-use conditions are met? Could the
integration of REMS into health information systems ever reduce or eliminate the need for
other REMS tools, such as provider education?
Hospitals, clinics, physician offices, pharmacies, distributors and wholesalers each have their own health
care information system technologies. The health care industry has not settled on a standard set of
EMRs or other health care systems. With each approved REMS program, a series of information systems
and manual tools are designed to support the individual requirements of the specific REMS.
Disparate EMR and other various health care information systems increase the complexity as well as the
implementation and operational costs of each individual REMS program. This is particularly
burdensome for clinics and hospitals, as they may be supporting multiple REMS and are overly-
burdened with implementing individual point solutions. Each approved REMS imposes enormous costs
on the sponsors as well as on the broader health care system. An integrated, consolidated, universal
REMS management system potentially would ease adoption, lower costs and increase data consistency
and quality.
The REMS platform would consist of a Customer Relationship Master (CRM) cloud-based architecture to
manage a central repository of HCPs and patients, collecting and managing enrollment, training,
attestation, certification, surveys, adverse events of special interest, medical records, and any other
ETASUs , as required by REMS
The solution would support multiple intake channels, including mobile, web and direct real-time
integration/interfaces to support physician offices, clinics, hospitals, pharmacies, distributor and
wholesalers.
The solution would support the following views/portals, based on the stakeholder:
Patient Portal – This portal would include enrollment, attestation, surveys, risk disclosure and
other supporting information.
HCP Portal – This portal would include enrollment, attestation, surveys, risk disclosure and other
supporting information. It would be web-based and have a real-time interface.
Hospital Portal – The portal dedicated to hospitals would cover enrollment, certification,
surveys, HCP management, risk disclosure and any other supporting information. It would be
web-based and have a real-time interface.
Distribution Portal – This portal would provide real-time approval to sell products with a
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Specific comments
controlled distribution ETASU. It would be web-based and have a real-time interface.
3. Many stakeholders have suggested that a single Web portal should be established to act as a
repository for standardized REMS tools and materials and to serve as a central information or
reference source for REMS stakeholders. What barriers exist for the development of a single
REMS Web portal? Who would be responsible for developing and maintaining the Web portal,
and what role would FDA play?
To undertake the development of a REMS platform, we recommend the creation of a consortium that
includes various stakeholders (e.g., FDA, biopharmaceutical companies, hospitals, clinics, pharmacists
and patient advocacy groups) who have a voice in the design and implementation of the portal.
From a technological standpoint, we do not see any significant barriers, although a challenge will be
ensuring the timely adoption of the portal and agreement on real-time integration standards. To ease
implementation issues, we recommend using a phased approach that initially focuses on web and
mobile interfaces, followed by direct integration to a cloud-based architecture. For more details on the
proposed solution, please refer to the response in D.2.
E. Approaches To Assessing the Impact of REMS
Drug manufacturers are required to submit assessments of their REMS on a regular basis. To date, these
assessments have tried to evaluate the effectiveness of the REMS by measuring the frequency of
adverse outcomes of interest, the knowledge of stakeholders, and the compliance of stakeholders with
certain REMS requirements. To accomplish this, drug manufacturers have relied on spontaneous
adverse event reporting, knowledge surveys, and systems that track stakeholder completion of certain
activities, such as enrollment and documentation of safe use conditions. To improve how REMS are
assessed, FDA is considering additional areas for measurement and additional methods to measure the
impact of REMS.
1. Should FDA routinely ask sponsors to assess the overall impact of their REMS on prescriber,
dispenser, and patient burden, and/or access to the drug? If so, how could drug manufacturers
assess the REMS impact on access and burden?
The overarching objective of REMS is to minimize specific risk(s) of a medicine so that the medicine’s
benefits outweigh its risks. To achieve this objective, REMS activities should be focused on activities
that lead to minimization of the risks(s) (e.g., requiring pregnancy testing to mitigate teratogenicity risk).
However, while most RiskMAPs clearly identified a risk that could be mitigated by a variety of activities,
many REMS either identify risks that are difficult to mitigate or focus on activities whose impact on the
risks are difficult to measure. Thus, it will remain challenging to evaluate the effectiveness of REMS that
are focused on risks that cannot be mitigated or activities that do not have a direct connection to risk
reduction/elimination.
Beyond the consideration of effectiveness, the efficiency of REMS is also an issue. While REMS can be
an important component of risk mitigation activities, they inadvertently create an administrative burden
for HCPs, and any methods used to adequately assess this burden with objective data will be
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challenging. To solicit feedback from HCPs regarding this burden would only further add to the
administrative burden on HCPs, and adding to the administrative burden ultimately has the potential to
hinder appropriate patient access.
Thus, in considering ways to efficiently and effectively mitigate the risk without needlessly hindering
patient access or adding administrative burden, FDA’s goals for REMS should be three-fold: to ensure
REMS activities are linked clearly and explicitly to risks that can be mitigated/eliminated and that the
risk mitigation effect can be measured; to simplify any REMS materials and associated processes; and to
move expeditiously to minimize or eliminate REMS, where appropriate.
2. What methods might be used to separate the impact of a REMS program from that of other
related risk management activities? Without having a control group, how should FDA interpret
and act on REMS assessment information?
Since REMS are required by the FDA but not by other regulatory authorities, one method to evaluate
whether REMS are impacting drug safety would be to compare the experience of the drug in the US with
the experience with the drug outside of the US. For instance, one could compare whether the rates of a
given risk are the same or different in the US versus outside of the US. Also, one could analyze the
results of clinical trials and the data from the drug sponsor’s global safety database to see if there are
any signals from these activities.
3. It is possible to interpret evidence of sustained REMS effectiveness to mean that the REMS
should be maintained indefinitely, but such evidence may also suggest that safe use of the drug
is now ingrained in the health care system and that the REMS can be modified or eliminated.
What evidence could help FDA determine whether a drug would continue to be used safely if
the REMS were modified or released?