Page 1 of 13

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

Page 2 of 13

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

Page 3 of 13

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,

Page 4 of 13

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.

Page 5 of 13

Specific comments

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

Page 6 of 13

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.

Page 7 of 13

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

Page 8 of 13

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

Page 9 of 13

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?

Page 10 of 13

Specific comments

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

Page 11 of 13

Specific comments

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

Page 12 of 13

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

Page 13 of 13

Specific comments

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?