meeting transcript (7/26/13) (pdf - 3.4mb)

FOOD AND DRUG ADMINISTRATION

+ + + + + STANDARDIZING AND EVALUATING RISK EVALUATION

AND MITIGATION STRATEGIES (REMS)+ + + + +

PUBLIC MEETING + + + + +

FRIDAY

JULY 26, 2013

+ + + + +

The Public Meeting convened in theFDA White Oak Great Room, Building 31, Room1503, 10903 New Hampshire Avenue, SilverSpring, Maryland 20993, at 8:30 a.m., TheresaToigo, Panel Chair, presiding.FDA PANEL

THERESA TOIGO, R.Ph., M.B.A., AssociateDirector for Drug Safety Operations,Panel Chair

CDR CHARDAE ARAOJO, Pharm.D., M.S., DeputyDirector, Office of Medical PolicyInitiatives

DORIS AUTH, Pharm.D., Lead Pharmacist,

Division of Risk ManagementMICHIE HUNT, Ph.D., M.B.A., Program Analyst,

Office of Executive ProgramsMWANGO KASHOKI, M.D., M.P.H., Associate

Director for Safety, Office of New DrugsADAM KROETSCH, M.S., Operations Research

Analyst, Office of Program and Strategic

Analysis Neal R. Gross & Co., Inc.

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ELAINE LIPPMANN, J.D., Regulatory Counsel,

Division of Regulatory Policy IICLAUDIA MANZO, Pharm.D., Director, Division

of Risk ManagementMEGAN MONCUR, M.S., Regulatory Health Policy

Analyst, Division of Risk ManagementGARY SLATKO, M.D., Director, Office of

Medication Error Prevention and Risk Management

CAPT MARCIA BRITT WILLIAMS, Ph.D., TeamLeader, REMS Compliance Team

MARY WILLY, Ph.D., Associate Director,Division of Risk Management

SPEAKERS STANDARDIZATION PROJECTS SPEAKER SECTION GERALD K. MCEVOY, Pharm.D., National Council

for Prescription Drug Programs (NCPDP)C. DOUGLAS MONROE, R.Ph., M.S., Kaiser

Permanente YOLA MORIDE, Ph.D., F.I.S.P.E., Universite de

Montreal MARIE LINK, Pharm.D., REMS Logic, L.L.C.CATHERINE SIGLER, D.V.M., M.P.H., Ph.D.,,

United BioSource CorporationFRANK GALLO, Pharmaceutical Product

Development, L.L.C. (PPD)MADALINA CHIRIEAC, M.D., M.P.H., Biogen Idec,

Inc. REBEKAH L. HANSON, Pharm.D., B.C.P.S.,

B.C.A.C.P., University of Illinois atChicago

Neal R. Gross & Co., Inc.202-234-4433

GENERAL EVALUATION SPEAKER SECTION SARAH A. SPURGEON, Pharmaceutical Research

and Manufacturers of America (PhRMA) MEREDITH Y. SMITH, Ph.D., M.P.A., AbbVie,

Inc.

GRETCHEN S. DIECK, Ph.D., United BioSource Corporation

MARC DELUCA, M.H.S.E. candidate, Lehigh University and ParagonRx International, L.L.C.

M. KRIS SRINIVASAN, M.D., M.B.A., M.H.S.E., ParagonRx International, L.L.C.

RUTH S. DAY, Ph.D., Duke University SIDNEY S. WOLFE, M.D., Public Citizen JULIANE K. MILLS, M.S., M.P.H., United

BioSource Corporation Neal R. Gross & Co., Inc.

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C O N T E N T S

Opening Remarks 5 Standardization Projects Speakers 13

Standardization Open Public Hearing 124

REMS Assessments: A Summary of FDA's

Experiences and Challenges 133

Building a Framework for Future REMS

Assessments 145

General Evaluation Speakers 162

Meeting Summary 269

Closing and Adjournment 280 Neal R. Gross & Co., Inc.

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Page 5 P-R-O-C-E-E-D-I-N-G-S

8:32 a.m. MS. TOIGO: Good morning, and

welcome to day two of our public meeting on REMS standardization and evaluation. Good morning to the attendees in the room, and to those joining us by webcast.

I'm Terry Toigo, and I'm the Assistant Director for Drug Safety Operations in the Center for Drug Evaluation and Research. And I will be your moderator, and I also chair the FDA panel.

So before I start, can I just have a show of hands for people who are new today, who didn't join us yesterday? Okay, so we do have a few, but we'll still do the condensed version of the opening.

Okay, so just some housekeeping, we have two open public comment sessions, one in the morning today at the end of this panel, which we set up to cover standardization for those who want to comment publicly on


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Page 6 standardization and didn't sign up for one of the panels. So now is last call for you to sign up for that session of the open public hearing. Or actually, you can do that before the break, which is at 10:30 this morning.

Lunch today will be 12:15 to 1:15, same as yesterday, sandwiches, salads, beverages in the lobby, and hopefully they won't run out of Diet Coke, since that seemed to be the big seller yesterday.

Next, just to kind of remind you what to expect for today, the purpose of the meeting, again, just to kind of set the stage, is to create a forum for interested stakeholders to provide input about REMS.

And specifically, the Federal Register notice stated that we are looking for feedback on standardizing and assessing REMS, and also for suggestions about potential projects that will help standardize REMS, and integrate them into the health care delivery system.


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Page 7 And actually, this morning's

panel, that's pretty much, based on what we got from the outlines, that's what we think this panel is going to address. They're either going to talk about proposed projects, or they're going to share some things that they've done in their institutions that we can think about.

So the format -- yes, and importantly, these meetings meet our PDUFA performance goals. So the format for today's meeting, FDA presenters will begin the evaluation discussion. We did the overview of standardization yesterday, but we'll have two presentations on evaluation this morning.

Dr. Willy will go and give us --kind of look back at some of the evaluation --assessments that we've been doing, and then Dr. Slatko will look forward with evaluation, and present some of the thinking that we've been doing related to that. And I encourage you, if you haven't read the background


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Page 8 document, to please do so.

We spent a lot of time looking back at REMS, and what we've been doing over the past few years, to compile something that we think will be helpful for stakeholders, and it -- the other purpose is to kind of stimulate your thinking, and for us to solicit more feedback through the docket. So we hope that background document will provide a guide to help you do that.

So then after the FDA, or our stakeholder panel, actually, they're going to provide input on the questions from the Federal Register notice, and comment on some projects, and then we -- our FDA panel and many other FDA staff in the room, will be listening to the panel presentations, and will be asking questions.

We also have been taking notes over the past -- took a lot of notes yesterday, and we'll do some more today, and the intent, at the end of the meeting, is to


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Page 9 summarize, high-level summarize what we --what we think we heard from stakeholders. Not -- won't be exhaustive or comprehensive, but we've been carefully listening, and we'll try and do a little bit of a wrap-up at the end of today's meeting.

And Gary Slatko chairs the evaluation and the standardization working groups, and so he's -- he's the designated wrapper upper. So, but he's been helped by people providing things that they've heard throughout the -- throughout yesterday.

So as you can see from the agenda, we have the two FDA presentations that I mentioned, and then there are 16 stakeholders for us to hear from today, and they're in two panels. And just to remind the speakers that you -- each speaker has been given a ten minute slot.

I've looked at some of the slides, and maybe not this panel, but the later panel in the day, there's lots of slides, and I'm


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Page 10 going to be curious how people are going to get through it in ten minutes.

But again, we are not putting --the microphone will not turn off at ten minutes, but at ten minutes you'll see the red light blinking, and I'll let you go over a little bit, but then at some point I'll kind of give you a little look and ask you to finish up if we go over ten minutes. So that's how we're going to handle that, rather than cut you off at the microphone.

And let's see -- last thing, I think -- the room is a little bit warmer now. People were complaining about cold yesterday. We tried to adjust the temperatures. Hopefully it's better for everybody today, but you know, there's some things we really can't control related to the meeting. So we're doing our best to accommodate people's concerns, but we may not get it right.

And so if you were here yesterday -- suggested for those that were really going


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Page 11 to -- were really cold, to bring your own blanket, because that's about the only thing we can do for cold.

So with that, I think we, I want the FDA panel members to introduce themselves so that you know who your listeners are up here, but there are a lot of listeners out there, too. So, Dr. Slatko.

DR. SLATKO: Good morning. I'm Gary Slatko. I direct the Office of Medication Error Prevention and Risk Management within CDER.

MR. KROETSCH: Hi, I'm Adam Kroetsch. I'm in the Office of Program and Strategic Analysis in CDER.

DR. WILLY: I'm Mary Willy. I'm the associate director in Division of Risk Management.

DR. AUTH: I'm Doris Auth. I'm the team leader on the Assessment Team in the Division of Risk Management.

MS. MONCUR: Good morning, I'm Neal R. Gross & Co., Inc.

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Page 12 Megan Moncur, and I'm also in the Division of Risk Management.

DR. HUNT: Good morning, I'm Michie Hunt. I'm in the Office of Executive Programs, and the project manager for the REMS Integration Steering Committee.

DR. KASHOKI: Hello, my name is Mwango Kashoki. I'm the associate director for safety in the Office of New Drugs.

Dr. MANZO: Good morning, my name is Claudia Manzo. I'm the director of Division of Risk Management.

DR. ARAOJO: Good morning, my name is Chardae Araojo. I'm the deputy director of the Office of Medical Policy Initiatives.

MS. LIPPMANN: Hi, I'm Elaine Lippmann, regulatory counsel in the Office of Regulatory Policy.

DR. WILLIAMS: Good morning, my name is Marcia Williams, and I'm on the REMS Compliance Team, team leader in the Office of Compliance.


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Page 13 MS. TOIGO: Okay, I think that's

our FDA panel. So we'll get started. Gerry McEvoy's going to be our first presenter, and representing the National Council for Prescription Drug Programs.

DR. McEVOY: Thank you, and good morning. I'm here today representing the National Council for Prescription Drug Programs as lead of their SPL REMS Requirements Task Group, which NCPDP formed in May of 2001. I am one of approximately 1,600 stakeholder volunteers that regularly participate in NCPDP's standard development activities.

NCPDP is an ANSI-accredited standards development organization that has been working collaboratively with FDA through one of its many workgroups for over four years, in advising the agency of the potential enhancements to structured product labeling, or SPL, that focus on meaningful downstream uses of these data by the healthcare


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Page 14 information technology sector.

It was from this collaboration that arose the recommendation in November, 2010 to investigate the merits of using SPL as the preferred path for capturing and representing REMS data in a highly structured and codified format suitable for automated extraction and incorporation into various electronic applications.

Recognizing the critical importance of first establishing a standardized electronic data structure and codification mechanism for REMS data, NCPDP's board designated the SPL task force as the lead for its other REMS activities in August, 2011, including all aspects of prescription processing, from the point of prescribing, to ultimate receipt of the drug by the patient, as well as associated authorization messaging, tracking, and reporting.

In my day job, I am assistant vice president of drug information at the American


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Page 15 Society of Health-System Pharmacists, and therefore, ASHP clearly supports the leveraging of SPL as a means for standardizing REMS data.

Beginning with Adam Kroetsch's excellent summary of the role of SPL in REMS standardization at the beginning of this meeting, to subsequent endorsements from other groups yesterday, I will now attempt to summarize in my comments why NCPDP and a broad base of stakeholders believe that SPL is the preferred path for REMS data standardization.

Such standardization of data, codification, and structure, is absolutely critical for downstream automated solutions directed at seamlessly integrating REMS into health-system workflow, and greatly reducing the current burden, which is heavily weighted by manual, and often redundant, non-interoperative processes.

At the outset, let me clarify that SPL is far more than simply an electronic file


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Page 16 of professional prescribing information, what commonly is referred to as labeling, or the package insert.

Instead, it has been positioned by FDA to continue to expand into a robust repository of highly-structured data about drugs, and their associated products, that drive a myriad of automated processes and applications, including integrated ePrescribing and prescription processing systems, and alerting, and other safety mechanisms.

So again, NCPDP is an ANSI-accredited standards development organization, and the focus on its recommendation for SPL is actually linked to several of its existing standards.

So NCPDP currently has three task groups working on REMS. The task group that I lead, that deals with SPL, there's a task force that is looking at its integration into ePrescribing, and finally, there's a task


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Page 17 group called the Safe Use Processing Task Group, that's looking at its integration into the prescription transaction process. So all components of prescription authorization, claims adjudication, and reporting standards.

The need. There currently is no highly-structured electronic REMS submission requirement. Electronic versions of REMS are simply PDFs, and word processing documents. And while they may follow a structured outline, they are not documents that are readily extractable to drive automated applications.

There currently is no standardized granular data structure, there is no standardized coding mechanism, and there is no codified connection with labeling. If you search DailyMed to try to identify drugs that are subject to REMS, you will fail. When a lot of them had Med Guides requirements, you could do a surrogate search and search for Med Guides, and you'd at least find those, but the


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Page 18 term REMS is not even used in labeling.

And in addition, there's no codified link. And one of the initial steps that could be taken, is to simply add, as a limitation use identifier, that a drug is subject to a REMS. And that currently exists as an opportunity within SPL.

There also is no method to electronically and -- identify and extract REMS requirements for meaningful use, and the most important thing is that downstream automated prescription authorization and processing requires highly-structured, codified REMS data to operate efficiently, in a timely fashion.

So the proposed solution is to use SPL as a highly-structured, granular mechanism for REMS submission, maintenance, ready access by all potential users, and meaningful use. By applying data format, content, and coding standards. By using SPL access via DailyMed to allow meaningful data extraction, again, by


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Page 19 all potential users, including electronic applications developers.

And to develop standards focused on REMS requirements verification for transactions, again, in the workflow environment, for seamless prescription processing, claims processing, reporting, and many other functions.

Why use SPL? Well, there is a need for incorporation into workflow, and to minimize the burden for prescribers, pharmacies, and sponsors, and others, that SPL could easily meet. There's the need for a reliable, standardized source, with required elements to safely and effectively use medication. Again, SPL would meet that need.

REMS information can be extracted easily, automatically, and electronically, from an SPL document, and most importantly, patients and their safety, as well as access -- timely access to REMS, are the most important reason to standardize REMS


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Page 20 information to the SPL.

SPL is an existing, adaptable standard already in wide use for exchanging meaningful medication information electronically. It's well-suited for highly-granular data like REMS. SPL formatting allows a mix of coding and text, and it's a highly-adaptable substructure.

Yesterday, there were a number of comments that if we standardize, we're at risk of losing distinctions, important distinctions, that may exist between one REMS and another. And with SPL, that is not a limitation. It's a very highly-adaptable structure. So if something new occurs down the line, it can be readily accommodated in the structure of SPL as a modification.

There are existing mechanisms for addressing issues, best practices, new developments, new needs, standards, and future development. There currently exists effective, publicly accessible data repository, via


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Page 21 DailyMed.

There is a large cadre of existing expertise and infrastructure to support it, and sponsors have extensive experience in submitting SPL data electronically to a central repository with their prescribing information and other information that's included in SPL.

Where can the standard be derived? NCPDP did an initial development of a schema that was drawn from the draft guidance on REMS, and we've been working very closely through NCPDP with FDA, and FDA subsequently identified data requirement gaps relative to the draft guidance that would create an internal database that can be used as a foundation for structuring an SPL REMS data standard. As I mentioned before, SPL is an existing, adaptable, HL7 standard. So we don't have to create something new.

Why standardize? Codification of unique components with SPL is a way to


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Page 22 organize, standardize, and centralize the content associated with a packaged product. So you can do it all the way down to the NDC level if you need to.

And there are some products where the REMS is actually indication specific. It's not tied to a specific generic drug, but it's tied to a specific use within the label of that drug. So again, SPL is well-suited to make those distinctions in an automated sense.

It would standardize REMS format and content for electronic submission to the FDA. The standardized granular REMS requirements would simplify integration into ePrescribing applications and prescription processing systems. A standardized REMS format allows easy inclusion within existing standards, and allows automated population.

I see that I'm running out of time, so let me skip to the recommendations. So our recommendations -- the benefits are that it will be a more efficient submission,


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Page 23 and all of the processing required.

And NCPDP wishes to continue to collaborate with FDA in moving this initiative forward, and our recommendations -- this is my last slide -- is to adopt SPL as a means for standardizing and providing central access to REMS data, to designate development and implementation of SPL standardization of REMS as one of the four PDUFA V priority projects, and to designate NCPDP, the National Library of Medicine, and others, potentially as collaborators, to continue the ongoing work. And I thank you.

MS. TOIGO: Thank you, Gerry. Our next speaker is Douglas Monroe from Kaiser Permanente.

MR. MONROE: Good morning. I'm Doug Monroe. Thank you for the opportunity to speak about approaches to standardizing REMS tools. I'm a drug information pharmacist at Kaiser Permanente, and among my areas of focus are specialty pharmaceuticals and REMS. I have no


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Page 24 relevant financial interests to disclose other than my employment.

As the largest healthcare delivery system that's integrated in the United States, Kaiser Permanente includes providers, hospitals, 37 of them, positions, more than 16,000, nurses, pharmacists and other clinicians, as well as regional health plans.

In addition to more than 440 pharmacies, we have one Kaiser Permanente specialty pharmacy that serves all of our regions. This map shows the regions served by Kaiser Permanente, extending from here in what we call the Mid-Atlantic region, all the way to Hawaii, which you can see is near Alaska, south of Texas.

At Kaiser Permanente, we have experience with approximately 30 REMS, which include ETASUs. Of those, about 16 REMS, with various types of ETASU, involve multiple dispensing sites, and ten such drugs are dispensed by our Kaiser Permanente specialty


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Page 25 pharmacy.

In the light of our REMS experience, when we evaluated opportunities and barriers for developing standardized REMS tools, we identified several recommendations. I'll mention those briefly, and then focus on one area in particular.

First, we look forward to participating in an open, collaborative, multi-stakeholder process to design and standardize REMS tools. We support a central repository for REMS documents and tools. We favor more standardized approaches to training, which could include stepped training.

Knowledge pre-assessment would take advantage of us specialist prescribers' existing knowledge, and expedite prescriber training. Pass the test, and go straight to summary and certification.

Training should be updated with information from REMS safety findings and


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Page 26 assessment results, both of which could be made public, with a goal of sharing learnings and improving safety.

REMS protocols should limit the collection of protected health information, or PHI, to the minimum necessary, and that should be clearly stated in the REMS documents.

As an enhancement to REMS documents, the use of a summary table at the top of each detailed REMS document could provide easy-to-grasp standard sets of key information, such as who must be trained and registered, what will be monitored, et cetera.

And, bolded here for emphasis, as the item which I'll address most specifically today, REMS should explicitly permit existing distribution systems to dispense if they can meet or exceed requirements. That'll be especially important in considering the second set of questions proposed in -- posed in this section.

In response to the question, how Neal R. Gross & Co., Inc.

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Page 27 might health information technologies, or HIT, such as electronic health records, or EHR, pharmacy management systems and electronic prescribing systems be used to integrate REMS into existing healthcare settings, FDA should look at how currently established systems and practices are already developing and using REMS tools in an advanced HIT environment.

As an example, Kaiser Permanente's specialty pharmacy developed software additions to our pharmacy information management systems that access electronic tools like EHR documents, and computerized physician order entry, and we call this software SPIMS.

Her is one screen shot illustrating some of those capabilities. The pharmacist screen includes the following. Automatic retrieval of lab results, focused display, at the bottom of the screen here. For specified labs, depending on focus drug, highlights and alerts for out-of-range


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Page 28 results, and notices to the pharmacist when a lab is due or overdue.

In addition, the tool can display diagnosis information, prescription history, current prescription details, prescriber notes, treatment plans, counseling templates, shipping and logistics information, and custom design screens to pull in or document other important information.

As another example, refill dates can be automatically calculated to alert pharmacists to check for adherence, for example by calling the patient and discussing how many doses he or she has left.

And this can lead to advising the patient on adherence measures, helping patients in managing side effects, beginning the refill process, and all with overarching coordination with prescriber notes, treatment plans, scheduled office visits, because that's where dosage and medications are most likely to be changed.


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Page 29 Integrated healthcare systems are

designed to deliver coordinated care by linking providers to each other and to patients, across all transitions of care, often supported by HIT systems.

This linkage and intercommunication are an integral part of care experience for our members. And patient linkage is vital to our members, as well. Our members are now accessing Kaiser Permanente online tools more than 88 million times per year.

We heard yesterday several observations about how limited distribution leads to fragmentation of care when it removes the dispensing and management of a REMS drug from an integrated care system. The point has been well made that interruption of coordination across transitions of care creates new problems for access and safety.

To be clear, distribution limitations are not REMS requirements. REMS


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Page 30 themselves do not fragment care. Limiting distribution to one or a few specialty pharmacies, however, is usually rationalized as a means of assuring the REMS requirements are satisfied. But when an integrated healthcare system can satisfy those requirements without compromising outcomes, this rationalization is not logical, to quote Mr. Spock.

The following shows why this can be important. Let's take the example of a drug approved under a REMS with an ETASU that was required because the drug showed cardiotoxicity during qualifying clinical trials. For example, QT interval prolongation, arrhythmias, sudden death, and so on.

If basic ETASU requirements, on the left here, are to assure that the prescriber has completed training, or to provide educational material, then virtually any pharmacy with access to REMS hub can perform that function. However, a specialty


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Page 31 pharmacy inside an integrated system, with electronic tools, can provide an advanced level of support for the prescriber or patient.

In this example, the pharmacist can check electrolyte balance, verify that recommended EKGs have been done per schedule, and monitor for new prescription drugs with potential interactions, for example, drugs that also prolong QT interval.

We're concerned that limiting distribution means removing important safety measures like this, and the result can be lower safety surveillance standards in contrast to the purpose of a REMS. So we recommend that REMS explicitly state that access to a drug or dispensing will not be limited or restricted for healthcare systems or pharmacies that are able to demonstrate they meet or exceed REMS requirements.

Finally, on the question of a single web portal, we recommend as part of the


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Page 32 standardization of REMS that the source of tools and information about REMS should also be standardized under the aegis of the FDA.

An excellent source of information already exists of the FDA site for concise REMS documents, and the most logical and practical solution would be to incorporate all FDA-approved materials into a single centralized resource center, thus eliminating the need for prescribers to find and access a separate sponsor-based website for each medication that has a REMS with ETASU. Simplicity, clarity, and easy access.

We see opportunities and challenges for standardization, and we hope our recommendations and illustrations here help to demonstrate how REMS might be improved through standardization.

Thanks for listening. I look forward to responding to any questions during the Q&A period.

MS. TOIGO: Thank you, Doug. Our Neal R. Gross & Co., Inc.

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Page 33 next presenter is Yola Moride from the University of Montreal.

DR. MORIDE: So good morning. I am here to represent the Council for International Organizations of Medical Sciences, commonly known as CIOMS. So what I will present to you this morning is a summary of the initiative of CIOMS Working Group IX, which is on the practical considerations that the development and application of a tool kit for medicinal product risk management.

So what is CIOMS? CIOMS is an international NGO that was created in 1949 by the WHO and UNESCO to facilitate and promote international activities and harmonizations in the field of biomedical sciences. The CIOMS working groups frequently involve senior scientists from regulatory authorities, academia, and the pharmaceutical companies.

As part of the activities of the various working groups are the publication of consensus reports, such as the CIOMS Working


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Page 34 Group IX. So the scope of the Working Group IX is the consensus report discussing risk minimization tools for managing the risks of medicinal products intended for human use, best practices in the tool development, and considerations governing the potential application of these tools. The publication of the consensus report is expected at the end of this year or early next year.

A stakeholder perspective has guided the content of the report that will cover the following areas. Prescriber-directed REMS tools, patient-directed REMS tools, REMS tools and drug-dispensing settings, approaches to standardizing the REMS tools, as well as approaches to assessing the impact of the various REMS.

The objective is really to consolidate concepts of risk management tools, and propose their application in order to harmonize the views, and to positively impact the prescriber patient interactions, and


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Page 35 globally protect the public health.

The goal -- the working group states that the goal of a risk minimization program would be the same globally but using shared systems, although it acknowledges that locally different tools could be used to achieve the same goals.

So a brief summary, which can be appreciated through the currently planned table of content. So the consensus report will include introduction, scope, and background of risk minimization, the current landscape, the principles for the identification and applications of risk minimization tools, evaluating and the methods to be used in the evaluation of the effectiveness of risk minimization tools, the governance and points of implementation, stakeholders in risk minimization, current trends and future directions, as well as recommendations.

In addition, an appendices, there will be a glossary of terminology, real life


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Page 36 examples, survey on broader stakeholders' input, a decision tree for the selection of REMS, risk minimization with vaccines as a specific topic.

So as a general comment, CIOMS Working Group IX acknowledges the pivotal role of the healthcare system as a vital component in medicine safety, and recommends that undue burden on such a system should be avoided whenever possible when planning and implementing risk minimization and mitigation strategies.

Now from a personal, academic perspective, in my opinion, standardization --two prerequisites are associated with harmonization and standardization. Transparency and highest methodological standards. So transparency, I would urge to increase the publication of results of evaluation of REMS effectiveness, either in the scientific literature or registries that are specifically dedicated for that purpose.


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Page 37 From a methodological viewpoint, I

also urge to use best practices in mainly two domains: pharmacoepidemiologic research, for example the ISPE Guidelines for Good Pharmacoepidemiology Practices, as well as best practices in evaluative research.

And finally, a caution is that we need to avoid that the assessment tools become risk minimization tools themselves, otherwise it biases the assessment. Thank you.

MS. TOIGO: Thank you. Our next presenter is Marie Link from REMS Logic.

DR. LINK: Hello, and thank you to the FDA. I value this opportunity, and appreciate it very much. I am president of REMS Logic, LLC, and I am a pharmacist, clinician first and foremost. I started in pharmacy 21 years ago, in 1992 with Revco Drug Store.

And I have since then gained a wide array of experience across various healthcare settings. Prior to my experience


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Page 38 with REMS Logic, I was employed for nine years by University Hospitals of Cleveland, Ohio, and served as their assistant medication safety officer. I was responsible for over 24,000 employees and 18 facilities.

During that time, I worked five years within the Quality Institute, alongside quality and risk management leaders, as well as those responsible to oversee and publish our national clinical compliance indicators. I have a strong understanding of healthcare data metrics, Joint Commission compliance, CMS, ACOs, meaningful use, healthcare reform, and national requirements.

My role reported directly to the leadership, the COO, the chief medical officer, the chief nursing officer, and the president of Quality. To allow an unbiased role and reporting opportunity for improvements in medication safety, I lead large scale standardization initiatives and integration efforts to improve medication


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Page 39 safety throughout, and focused on projects impacting 10,000 patients or more annually.

University Hospital's 900 bed main campus with six fully owned community hospitals, three joint ventures, 21 major outpatient centers, a revenue of 2.2 billion with 3.1 billion in assets, 93,000 discharges, 80,000 surgeries performed annually, and 4,000 physician providers, of which I had the opportunity to introduce to REMS requirements.

So with that, today I am here to share about REMS Logic, and introduce it to you. It is a centralized web-based portal for all REMS compliance. REMS Logic addresses prescriber, pharmacy, patient directed tools, as well as many well-thought-out suggestions, and requests and concerns that were presented yesterday.

REMS Logic is an integrative and facilitative model that accommodates the intricacies inherent with federal laws and requirements. However, it looks at the big


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Page 40 picture of what the end goal serves to accomplish, which is patient safety, medication safety, and allows something that is complex to be made manageable.

REMS Logic has honed in on a variation -- on the variation that exists among current REMS programs with the clear cut focus to streamline and optimize medication safety through evaluation of quality and effectiveness data to yield an infinite software versions, much like Twitter, Facebook, and LinkedIn, constantly emerging with the market that -- progress in line with healthcare quality advancement.

So variability, I want to share first a little bit of the clinical -- what the clinical team has collected to showcase the variability. I had to pick out some things quickly, so to really give a good example, so for 25 ETASU drugs we've broken out -

And I have Set A and Set B of our data to share with you, we have 11 patient


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Page 41 enrollment forms, 19 prescriber enrollment forms, 14 facility, and you can see the rest. Informed consent forms, seven, informed consent form names, are seven.

Set B of the data, counseling documents, eight, appropriate use checklist, six, brochures for patients, healthcare providers, we have ten different brochure names. There are 18 miscellaneous forms, some of which are prescription forms, and then there's just other types of forms. There's 15 different form names among them. Thirteen of pharmacy requirements.

So from the prescriber perspective, we have 25 ETASU drugs with 163 individual requirement details. This is a lot to manage, so how do we effectively do this?

This is just highlighting high-level progress over time with REMS changes, so we know that it's quite a dynamic process, and continuing to evolve throughout the years. This is recent, and then we heard yesterday


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Page 42 some July statistics that are even not on this slide.

So requirements for prescribers, what do they look like? We have all these different components for a prescriber to have to think about on any given day when administering or writing a prescription for a REMS medication, whether it's inpatient or outpatients.

We have ten different things highlighted here, and then we get to the healthcare organization and the pharmacy, which we often, even though REMS are prescriber-directed tools, there's a high impact on the pharmacy and the pharmacist to organize all these things, and then ultimately the organization to oversee compliance.

So we have medication guide distribution, staff education, verification of compliance by -- of the prescribers, enrollment of the facility, drug ordering, restricted distribution, loan borrow, patient


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Page 43 discharge, documentation, and audits. So a lot to think about.

So we want to think about standardization, and that's why we're all here. Standardization to improve integration. So what does that mean to the healthcare organization as the whole -- and all the stakeholders here? We need -- and this was a lot relayed yesterday, consistent naming nomenclature for -- for obvious reasons. We can't have seven informed consent forms with seven different names, however they imply the same meaning.

Categories. We need defined categories for elements of compliance. We need a standardized format and layout so that the prescriber can -- when they're looking for a specific requirement, if it exists or does not exist, they can reference a specific location to make that determination readily and quickly.

We also need, not only prescriber, Neal R. Gross & Co., Inc.

202-234-4433

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Page 44 but patient education options. I agree that they need to be CME and ACPE accredited to really comply with the current standard of expectation by clinicians of quality education that's unbiased.

And patient education options should also be more versatile in that they can be quick videos, but not so much reading material that's possibly not understandable or could be misinterpreted, but more in layman's terms.

So REMS Logic Technology, what is it? So this is a high-level focus, and I have ten minutes to share, but what we've done to standardize thus far is, on a strategic 30 foot thousand view, we have broken out into five categories.

We have general drug information, enrollment, education, training and monitoring, forms and documents, and pharmacy requirements. So these are the five categories that we have created for every single REMS


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Page 45 drug. So you log in, and this is what you find.

So under the five REMS categories, we have what is called a DSQ tool, which is a comprehensive, in essence, checklist, for the drug sponsor or REMS Logic staff, clinical staff, to manage on the back end, and within that, there are 37 subcategories which comprise all the various REMS elements that exist today among the current programs.

If you were to answer, yes, to all 37 requirements, okay, there's 81 potential details, requirement details, that are attached to those 37 subcategories. So as I showed earlier, we had 163 individual requirements for 25 ETASU drugs. So if you look at all REMS programs together, if all checkmarks were to say, yes, for all 37 subcategories, then you'd have quite a large amount of information to go through.

However, what we've done is we have created this comprehensive tool to make


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Page 46 sure that we've left no question or no stone unturned when we're evaluating a REMS requirement for an individual medication.

So what happens is the sponsor, drug sponsor, can log into the system, and they can go in and create the profile for their drug, and it prompts the drug sponsor to go through and answer every question yes, or no, or not applicable to each individual potential requirement that exists today among all the requirements that are out there. And it walks them through all five categories.

So on a large scale, what does the FDA REMS Logic -- or REMS Logic look like? How does it work? The healthcare organization enrolls their prescribers on the front end. The prescribers select the drugs that they use. The prescribers are made aware of the requirements, and they're prompted down a path to compliance.

The dashboard -- a prescriber has a dashboard for the drugs that they use


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Page 47 routinely, so they can have one-click access to whatever forms that they're needed. And the drug companies in turn, on the back end, can manage the drugs that they produce, and have security rights for their medications only.

And all of this is facilitated --so REMS Logic is truly a facilitation. Methods to assess efficacy. Absolutely thought of that. We have to have a lot of reports.

Ability to verify prescriber compliance will be in the tool trick, and reports, healthcare organization oversight, compliance and non-compliance, drug use statistics, prescriber activity -- and we'll be able to correlate prescriber compliance within -- with national medication error data to ultimately find out if we're successful or not.

So in summary, what is REMS Logic? REMS Logic is what TurboTax is to accounting. So it's a simplified tool to manage a complex federal requirement. TurboTax is to accounting


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Page 48 as REMS Logic is to REMS. Benefits -- and that's it. That's my contact information, and I look forward to hearing from you.

MS. TOIGO: Thank you, Marie. Our next speaker is Catherine Sigler from United BioSource Corporation.

DR. SIGLER: Good morning. My name's Catherine Sigler, and I'm senior director of safety, epidemiology, and risk management at UBC. UBC's been working in the area of risk management since 1999, and has been involved with many RiskMAPs and REMS.

Today I'm going to make the case that the risk management community, industry, academia, and regulators, have now had enough experience with REMS to be able to come together to create a best practices document. That we are having this workshop is a consequence of our current need for joint discussion with the common goal of shared experience, and a desired result of standardization.


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Page 49 To have the most rational

approaches, I advocate that we now join forces to document and learn from our mutual experiences.

So what is a best practices document? Simply put, it's a collection of knowledge regarding a topic with a focus on consensus opinion. Many of you will be very aware of these two examples of compilations of best practices, both of which represent large group efforts.

The first can be found on the website for the International Society for Pharmacoepidemiology, and was written to provide basic principles in conducting observational research. In many ways, it is an embellished checklist of items to be addressed and documented when conducting high-quality pharmacoepidemiologic and other observational research.

The second is a very useful book on the many considerations in designing,


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Page 50 conducting, and analyzing patient registries. It is particularly useful for individuals or companies whose primary experience lies in clinical trials. The unique considerations of registry designs are well-covered in this AHRQ publication.

Today and yesterday's workshop has a goal of sharing information about how to standardize and assess REMS. We are learning from each other and noting patterns. Perhaps now's the time to move beyond meeting transcripts and REMS case histories to the creation of a repository of best practices based on experience. That is, a best practices book on REMS.

You might say that everything REMS is quite an amorphous topic. Let's first begin the discussion on the types of information we might keep in a REMS best practices document. It's true, not all -- not one size will fit every REMS. They're quite different. How, then, can we generalize enough to write down


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Page 51 best practices?

Here's the basic approach I'm advocating. First, aim for a how-to focus with patterns based on experience. We would identify and then rely on lead authors with experience in key topics.

As an example, we could ask a project manager who has lived through the design, regulatory documentation, and operationalizing a REMS, to discuss milestones that might be planned to get -- and in particular, ETASU REMS, prepared in time for marketing.

For the creation of the book, we would use an approach similar to that of an NDA compilation within a company. That is, a collaboration with review, comment, and input by an experienced multi-disciplinary team guided by a time line.

Although I'm referring to the document as a book, as REMS are still evolving, it may be important to create this


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Page 52 new book to be more like a living document, perhaps keeping it primarily online, with planned additions and updates. The exact nature of the document would be a topic for an early organizational discussion.

Based on our experience at UBC, here's an early draft table of contents. It gives you an idea of the major topics that might be addressed in chapters. To call one out, I would say that drug distribution models are of great importance, particularly in ETASU REMS, whether retail or specialty pharmacy.

When still investigational, the timing of decisions regarding how a drug will be distributed might not be recognized within a sponsor's company as being a REMS issue. Certainly there are greater controls with specialty pharmacy distribution than in a retail setting, and these may facilitate or hinder a product's proper positioning, depending on the unique attributes of the situation.


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Page 53 A chapter on this topic, including

the considerations to be made in REMS design and drug distribution models, would provide readers with important points for consideration.

Here's a list of proposed next steps. I will summarize it as, first, a diverse participation from the various sectors, with participation, contributions, and leadership from, again, industry, academia, and regulators.

Secondly, it will require people's time, and we may need to find financial support. So certainly, particularly for academia, that would be important.

Thirdly, we would identify those who are willing to roll up our sleeves, convene the working group. Fourthly, begin to draft the document, bring it to life with a table of contents, by first agreeing on major topics. And I shared with you just some initial thoughts on that.


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Page 54 And fifth, get out a working draft

for the working group, and then wider review and comments. As with most projects, getting the timing right, not too fast and not too slow, would be critical. I would like to see that first draft completed a year from now.

I'm interested in discussing the level of interest in this project, and will continue to discuss with individuals who are working to design and improve upon REMS. Thank you for your attention.

MS. TOIGO: Thank you, Marie. Our next presenter is Frank Gallo, from Pharmaceutical Product Development.

MR. GALLO: Good morning, my name's Frank Gallo. It's a pleasure to be here, and I'd like to thank the FDA for this opportunity.

Prior to joining PPD, I worked on the manufacture side of the industry, and this presentation is going to talk specifically about multi-sponsor REMS programs, and


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Page 55 standardization there. And I -- when I was on the manufacture side, I managed and worked on programs that are now considered REMS. At that time, they were risk management, and then RiskMAP programs. And one of which was the first multi-sponsor REMS program.

So we're going to look at, specifically, the challenges around multi-sponsor REMS programs, and some areas where we could create standardization to support challenges being faced by that consortium of companies.

So as some disclosures, this is my point of view, not that of PPD necessarily, and not that of the companies that we represent, and we do represent companies in this area, and in clinical research in a range of areas. So that's our financial disclosure.

So specifically what we're going to look at it is first of all, the strong trend towards multi-sponsor REMS programs, and then the challenges that are being faced with


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Page 56 those programs, and some specific guidance that could be addressed jointly with the FDA to address those challenges.

Many of the challenges are clearly ones that the manufacturers need to address, and are addressing on a daily basis on their own, but there are areas where collaboration with the FDA would be helpful with items of standardization.

So first let's look at the drastic shift towards multi-sponsor REMS. And I assume everyone here knows what a -- for those of you that don't know, a multi-sponsor REMS is exactly what it sounds like. More than one pharmaceutical company working together on a shared program.

So prior to 2011, of the 178 products that were on the market under an approved REMS, over 97 percent of those were under single-sponsor REMS programs, and only a handful, less than three percent, were under a single shared system.


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Page 57 But if you look at today, there's

been a dramatic shift. So over 40 percent of the products with approved REMS are now under a shared REMS program with other companies, and only 56 percent are under single-sponsor REMS.

And we see this -- that this trend will likely continue to change, especially as many of the single-sponsor REMS programs start to get generic competition, it'll likely be that the generics and the single REMS programs will become shared programs.

So what are some of the challenges that these companies face when they're working together? And again, most of these challenges -- all of these challenges, they address as a working group, the first one of which is, the multi-company communication and processes, right? So you had these multiple companies coming together with regulatory, legal, medical operations, and they have to work across company to plan, develop, negotiate,


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Page 58 build, operate, and assess these programs.

And they're doing a very good job of addressing this, but that's a challenge. And they're competitors, so they have to be clearly avoiding any antitrust issues. And then once they had them up and running, there are always multiple vendors supporting these REMS programs. And so managing multiple vendors as a consortium of companies.

So these are some of the challenges that the companies are facing on their own, but we're going to dig in a little deeper to one area where we believe that there could be more standardization, and that's the impact of subsequent members to a program.

So once a multi-sponsor program is up and running, if the new product either has a pending application, or the FDA has determined that they need to now have a REMS, and it is to become part of a shared REMS, the process for alerting the members and integrating that program into a shared system.


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Page 59 Some of the specific items where

we believe there could be standardization. One is when a -- the notification. So when a new product is -- when the FDA has deemed that a product should join a multi-sponsor REMS program, if there was a standard process for notifying the applicable consortium as well as the individual company, so that there was transparency between the consortium, the FDA, and the company on that notification.

And then if the product is either already under an approved REMS, or it has a different individual REMS that has been submitted, the reconciliation process for integrating it into the multi-sponsor REMS.

Once that has taken place, the --the second area would be post-launch stakeholder communication. As we've seen with some of the presentations already, healthcare providers and patients, specifically healthcare providers in this case, are getting a lot of information on a number of different


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Page 60 REMS.

So what would necessitate, for example, a new healthcare provider letter to be added to the program based on the addition of a product, or an edited or revised healthcare provider letter, and when should those be sent? As part of annual mailings, or as companies join?

Because as generics are approved, or other brands come on, it's not uncommon for these programs to have new entrance into their consortium. And we need to make sure that we're not burdening or confusing the healthcare providers in the way we're communicating all of these changes as we go.

And finally, the integration of the programs into subsequent assessments. So obviously the new product has to be added to the multi-sponsor assessment plan, but depending on when that product joins the multi-sponsor consortium, it may not be practical to include them in that assessment,


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Page 61 period.

So should there be a standard time period? If a company joins within a certain amount of months before the next assessment period, then they should or should not be included in that assessment. And if that is the case, then are there any intermediate needs required for that specific product.

And that concludes my presentation. Thank you for your time.

MS. TOIGO: Thank you. Our next presenter is Madalina Chirieac from Biogen Idec.

DR. CHIRIEAC: Good morning. My name is Madalina Chirieac, and I am here today representing Biogen Idec. To speak to seven years of experience with our REMS program, for Tysabri in the U.S. And to address the question posed by FDA regarding which project could be carried out to standardize, not only the provision of risk information, but also benefit information to patients.


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Page 62 Tysabri is a monoclonal antibody

against alpha-4 integrins approved in approximately 70 countries to treat relapsing remitting multiple sclerosis and Crohn's disease in the U.S. It is associated with risk for progressive multifocal leukoencephalopathy, PML, an infrequent brain disease, brain infection, that usually leads to death and severe disability. And therefore, it has an extensive risk management program in place.

TOUCH prescribing program is a REMS with elements to assure safe use that has been implemented in the U.S. in 2006. Here are some of the key elements of the TOUCH prescribing program. We have a mandatory enrollment form that physicians as well as patients have to fill out at the enrollment in the program.

We have a centralized, or controlled centralized distribution process, which basically allows us to track every


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Page 63 single vial that we ship in the United States. We only ship to registered infusion centers that have been educated on the program, and that can attest that they will follow the requirements. And the program also offers educational capability to neurologists, infusion nurses, and the patients, as well.

Here are the key tools using the program and the corresponding stakeholders. The enrollment form. The medication guide that is distributed to patients at the enrollment in the program as well as prior to every infusion. The Pre-Infusion Patient Checklist that assesses for new neurological symptoms since the last infusion prior to every dose that has to be administered.

The prescribers also have two tools. The reauthorization questionnaire that is filled out every six months for the duration of the treatment, and the discontinuation questionnaire that has to be filled out by the prescribers six months after


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Page 64 the last dose of the treatment.

All this are basically monitoring for PML symptoms, and we -- and we feel that we actually emphasize a lot the risk that the product -- the potential risks for the product.

So we have been conducting REMS surveys, Knowledge, Attitude, and Behavior surveys, typical REMS surveys, every six months for prescribers for entry for the infusion centers, since the program inception. And we collected a lot of data, but we feel that these surveys have some limitations. They are only focused on the stakeholder understanding of the risk of the program. They lack the in-depth stakeholder review, and they are -- they include only the current participants in the REMS.

Therefore, we initiated the REMS stakeholder project in August, 2010. The research goals were largely inspired by the FDA public workshop that took place in July,


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Page 65 2010, and the project targeted getting insight on better understanding of the level of burden associated with REMS, assessing the effectiveness of tools, as well as assessing the effectiveness of communication aspects.

And a lot of the rest of the slides are going to be focused on emphasizing the effectiveness of communication aspects in REMS.

I also want to mention that we focused our stakeholder project on the MS population, which represents 98 percent of our patients enrolled in the TOUCH program, the rest of the two percent being the Crohn's disease patients in the U.S.

Let me try to give you an overview of the research approach and the methodology of the REMS stakeholder project. Because I think both -- over 700 participants, and I would like to start by saying that, in all phases of the project, we had participants from all stakeholder categories. Physicians,


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Page 66 infusion nurses, pharmacists, and patients.

Phase one of the program was the qualitative research phase, and it involves 63 participants. And the main goal of that was using individual interviews and focus group was to determine the key teams and areas of concerns around the REMS.

Phase two was the quantitative phase. That involved 645 participants. It was an online survey that was administered through the participants.

And Phase three was a drill down phase where we tried to -- we tried to get more detail on the teams that were identified in the quantitative phase. And that was conducted through interviews, as well.

This is one of the largest stakeholder projects that have been conducted. To our knowledge, there was only -- to date, there's only one comparable one in size, the NCCN, the National Comprehensive Cancer Network survey that was conducted in March of


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Page 67 2010.

An important point to mention was that, in our stakeholder projects, we included TOUCH participants, prescribers, infusion nurses, patients and pharmacies, as well as non-TOUCH participants, which have been provided to us from Quintiles, the vendor that we collaborated with to operationalize this project.

Now I would like to focus on what we found out about communication, and what type of information do stakeholders want to be communicated to them from a program like TOUCH, whose primary purpose is to provide risk information.

What we found out was that the majority want an equal balance between the benefit and risk information. We asked prescribers and patients, what would be the ideal balance of benefit and risk information for them in TOUCH, and ranging -- that was --the ranging on a seven-point scale,


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Page 68 information -- from a desire for all risk information, that is showed in red on the slide -- I'm sorry.

So a desire for all risk information, then in the middle column represents the equal benefit and risk information, that's presented in gray on this slide. I know it might be hard to see from the back. And to the right-hand side of the slide, it says, desire for all benefit information.

And as you can see, the majority of stakeholder wanted an equal balance between the benefit and risk information. It is presented here only for prescribers and patients, but similar percentages were for all stakeholder categories.

Then we wanted to drill down and see how would this change on the specific --on the specific element of the REMS. So we asked the same questions for the enrollment process, and as well as for the infusion, for the infusion process. And as you can see, the


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Page 69 majority of stakeholders wanted an equal balance between a benefit and risk communication to be communicated to them.

Further, we tried to drill down the question to specific -- to find out what, exactly, what type of information do patients want to receive from a program like TOUCH. And as you can see, they want to receive some risk information, they're higher percentages, but also, they want to see -- receive some benefit information.

They want to know if Tysabri is slowing the overall disease progression. They want to know how Tysabri can reduce the flares or relapses. All this are leaning towards the benefit information.

Based on our experience and the data presented, we feel it's important to stakeholders to include both benefit and risk information in REMS. This idea of including both benefit and risk information is similar to the informed consent process that has been


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Page 70 used in clinical trials.

And although there were some discussions about introducing benefit information in medication guides, we feel that we can go beyond that and include it in the enrollment form and other materials of REMS.

In order to assess this approach, we are proposing to conduct a pilot project in our REMS program that would have the benefit and risk information communicated as part of the enrollment form, as well as other medication guides, and other REMS tools.

The impact of addition of such information could subsequently be assessed using, for example, surveys or focus groups. We would like to engage with FDA to get input and endorsement for initiation of such a project, and I would like to thank the FDA for giving us the opportunity to present this data today. Thank you.

MS. TOIGO: Thank you. Our last speaker on this panel is Rebekah Hanson from


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Page 71 the University of Illinois in Chicago.

DR. HANSON: Good morning, everyone. And I'd first like to thank the FDA for inviting us to present today. I do really appreciate the opportunity to talk about REMS standardization.

Little bit about myself, so my current role at the University of Illinois is a clinical liaison pharmacist for specialty pharmacy service. I do have a dual role, however, at the University. This is where I work. It's beautiful.

So my second role is I provide clinical pharmacy services to the Pulmonary Arterial Hypertension Service that's part of the Institute for Personalized Respiratory Medicine in the Outpatient Care Clinic.

So essentially what I do is I provide ongoing medication management for patients with pulmonary hypertension, and it includes the entire gamut of medications that they use. And that also includes REMS


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Page 72 management. So I work with a prescriber and with a nurse to better, and ideally, more effectively, manage our patients.

So what I want to talk about today is one health system's idea of creating a tool to better standardize safety management for patients. So we're looking at safety management in general for ambulatory care settings, so this includes medications that have REMS, of course, which is why we're here to discuss this today, but also to manage other medications that may have safety related problems. Those with black box warnings and such.

So I'm going to present the pilot project that we are working through right now, and then in addition I'm going to talk about a couple of concepts that could potentially be applied to the larger initiative in REMS management.

One thing I do want to say is we are not yet live with this pilot project.


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Page 73 Unfortunately, we're working through some contractual issues, and are anticipating to be live shortly.

So before I move on, I wanted to mention, I heard a few comments yesterday from a few of the speakers that -- that REMS work, and that to change REMS would be a mistake. Well, I would like to provide a modified comment. I believe that REMS do work for some of the patients some of the times.

But unfortunately, there is inconsistency with REMS, and the current REMS programs, the way that they're built tend to promote fragmentation in care, and also restrict -- or, I'm sorry, they actually require polypharmacy to the patient, and most pharmacists know what polypharmacy means. It means a lot of different safety-related issues.

So what I wanted to do is provide a few cases. I'm going to speak about them very briefly, because of course I don't want


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Page 74 to take up too much time on this, but I thought it would provide a little background that served as our awakening at the University of Illinois to -- to work on the current process that we're working on.

So regarding Case 1, this was a 27 year old male with sickle cell disease who was seen through our clinic, and the decision was made to start him on ambrisentan, so of course a referral was submitted through the specialty pharmacy process, and it took eight weeks to get the medication initiated and accessible to the patient. And during that time, this particular patient had two urgent care visits because of worsening in shortness of breath.

Patient Case 2 was a 56 year old female who was started on Bosentan at our clinic. She came for her four week follow-up visit to do her routine blood work to assess her REMS required labs, and also to assess how she was doing with the medication. Well, we did see some abnormalities on her lab, so a


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Page 75 decision was made to continue the medication, but hold the dose at a lower dose. So normally you start at 62.5 and titrate up to 125 after the first four weeks depending on how they tolerate it.

Well, we made a decision to remain at 62.5, notified the patient, also notified the specialty pharmacy, and then continued to monitor the patient for a few weeks after that. After two weeks we had her coming in for labs.

Unfortunately, about ten weeks into the process, the pharmacy that was dispensing the medication, for reasons that are still unknown, made the decision that, during one of the REMS assessments calls, the dose was going to be increased to the 125, and did so, dispensed the medication to the patient.

It was identified during one of her routine follow-up visits, during medication reconciliation, that she was on an


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Page 76 increased dose, and we rechecked her labs, and notably, her hemoglobin dropped from 10.4 to 9.2 and the medication needed to be discontinued.

Patient Case 3 was a 33 year old female with child-bearing potential that was being managed for her pulmonary hypertension on ambrisentan and tadalafil. She presented to clinic one day reporting that she had a positive pregnancy test at home. And upon review of her medical record, we discovered that she was not being compliant with her follow-up for her pregnancy test monitoring.

And we also identified and discovered that the specialty pharmacy did indeed talk to her, and did indeed discuss with her the risks of teratogenicity, and asked her if the pregnancy test was completed, and she reported that yes, it was, and no she was not pregnant.

So during that time, she received one dispense at six weeks, and then also -- or


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Page 77 six weeks pregnant, and also the pharmacy was trying to coordinate that next dispense for her. The medication, of course, was discontinued immediately, and we initiated her on an infused medication, and unfortunately, this patient did pass away related to complications.

So what's our reaction to this? So our reaction was very similar to that of many healthcare systems. It's a knee jerk reaction. So what we did was increase vigilance and increase monitoring for our patients for ensure that the medications, excuse me, were not being dispensed until we had validation that those lab requirements and other safety monitoring was done.

So of course, this increased burden on the health systems. So herein lies what everybody is referring to as the excessive burden on the health system. So it required additional phone calls, paperwork, documentations. We had to limit prescription


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Page 78 refills to ensure that those labs were complete prior to dispensing medication. Of course, we were performing this with no additional resources, with no additional tools, and of course, suffering with continued fragmentation.

So what I want to talk about today is what we are trying to do to address the problem, to better manage our patients with these high-risk medications in an outpatient setting. And it was really a two-part process.

The first step was to formulate an outpatient medication safety committee that focuses on these high-risk outpatient medications. This is coordinated and lead by a medication safety officer.

Now, the whole purpose of this committee was to leverage the expertise and experience of our prescribers who manage these medications every day, to develop safe use, medication specific protocols for managing our patients.


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Page 79 And then of course, being led by a

medication safety leader, this position is responsible for not only managing the committee, managing the development of these safe use protocols, but then also managing REMS as it relates to outpatient use of medications.

So ensuring that the appropriate and proper education and training are being done, and that prescribers and patients are appropriately certified and referred.

So there are a couple of areas that we focused on with these safe use protocols. The first one is education and training as it relates to REMS and other risks related to these medications.

Also, adherence management. One of the most integral parts of safe use of medication is making sure that patients stay on the medication, and that they're adherent with their refills and their monitoring as it goes along, and also that they're staying


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Page 80 engaged with their medication therapy. It also involves safe use monitoring, which includes the required REMS components.

We also developed patient-centered disease and medication-specific indicators to be able to assess outcome related to the monitoring. And the whole goal was to improve communication, as well, both in and outside of the health system.

And what we did is take these safe use protocols that we developed that were medication specific, and implement them into a tool, a system, to help us improve efficiency and effectiveness with managing these patients.

So we took the setting from these protocols, and built them out into a workflow. And essentially what a workflow is is it can be a decision tree, a diagram of processes. It could be a questionnaire with branching logic. And all of those are included within our system.


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Page 81 It also might include checklists,

just to make sure that certain, certain things have been done prior to the medication being prescribed or being dispensed to assess appropriateness of use. It might also include generated tasks or follow-up management.

So it takes some of the burden off of the individuals that are managing the REMS, just gives them a dashboard and a tool to be able to know exactly what they need to follow-up on that day, instead of working on it in more of a reactive basis.

And then we also used this as a tool to improve adverse event reporting. Anyone who works in outpatient or ambulatory care knows that reporting adverse events is a problem. And a lot of adverse events go under-reported.

So we built in an assessment of adverse events for these patients to ensure that they're being captured, and then the responsibility of the leader, the medication-


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Page 82 safety leader, is to ensure that the adverse event reporting is occurring.

Of course, we're also using this to manage REMS compliance for our prescribers and our patients. Compliance reporting, measure outcomes related to those disease-specific and medication-specific indicators. And then of course use this to evaluate REMS program data. So being able to evaluate the labs that are captured during, during our safety management processes.

Goodness gracious. I'll be quick. I do apologize. All right, so I just wanted to show a couple of screen shots. So this is really the bulk of what our safety management system looks like. This is the case management tool.

This is one of my favorite slides, because it's a view to look at the time line of safety management. So this is -- the staff that's doing the REMS and safety management for the patient, doing the appropriate


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Page 83 monitoring and ensuring that validation and documentation of the processes -- or of these labs have been completed prior to authorizing a dispense of the medication.

And then this is a log function that we're able to generate -- pretty much anything that's entered into the system, we can generate into an external log to be able to improve communication both within and outside the University.

So some of the key concepts. Of course, this is not a new concept, you've heard it a few times already within this meeting, to develop an expert panel. So really leverage the expertise of the individuals that manage these medications.

And this could be through invitation or application. I do highly recommend that it's a multi-disciplinary committee that engages physicians, nurses, and pharmacists, and of course, absolutely the ancillary support staff that helps manage


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Page 84 these REMS.

And then also engages industry, pharmacy, information technology specialists, statisticians, and possibly even epidemiologists to be able to assess those outcomes. Could be tied to clinical research -- and I'll go on to the next one -- and then of course a REMS repository.

One thing I just want to point out about this is, could potentially use sample workflows for health systems, be able to better integrate this type of material into their system.

And then, the use of technology. I know that it's really a big endeavor to say, let's use one system for everyone, but one thing that I did think of is potentially this committee could provide technology roadmaps for people with their different electronic medical records in their system to be able to configure REMS management within their own health system.


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Page 85 And this is my conclusion. It

summarizes everything I talked about today, and I will wrap it up with these points. Thank you very much.

MS. TOIGO: Thank you, Rebekah. Okay, that concludes this panel, and we've got -- we built in extra time on this one for FDA questions, because we thought, based on the slides, there were going to be some details.

But I'm planning forward here and looking at what we've got, and I need a check -- did we get any open public speaker -- we do for standardization? How many -- one? Okay, so let's -- let's see how the questions go, and then we can play with the break and the FDA presentations, and a longer break, and a longer lunch.

But let's see how the questions go here, and we'll be flexible. So who wants to start? Doris.

DR. AUTH: Hi, my question is for Marie Link. I think yesterday I heard several


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Page 86 times that the FDA needs to create some sort of central portal, and I think everyone who mentioned that set you up really nicely for your presentation this morning.

And I was just wondering, maybe I didn't catch this in your presentation, but would this be something that could be used as a platform for enrollment of patients into REMS processes, into REMS programs, as well as submission of forms and any electronic verification of safe use conditions -- could it do everything that we need it to do?

DR. LINK: Yes, absolutely. It is set up -- it's actually built on an API, so it could also accommodate the SPL standardization labeling format, as well as -- it's built to have a -- capable to interface with EHR systems, and push out to the point of bedside care the necessary things that are needed at the bedside, as well as accommodate compliance while not caring for patients directly.

DR. AUTH: I guess just a follow-Neal R. Gross & Co., Inc.

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Page 87 up, what sort of challenges do you anticipate in managing that level of data with -- coming from so many different sources?

DR. LINK: I don't anticipate a huge, huge challenge. I mean, the technology is robust and able to -- it's really going to be more of an interactive interface between all the stakeholders, really. So it's a facilitation software engine that can be flexible and dynamic, because we know that healthcare and healthcare reform is not consistent, and that it's every changing.

So it's very much a dynamic tool that I anticipate will have, as I stated, multiple versions. And we know, today, that REMS are not where we necessarily want them to be, but we need to enhance them and optimize them to improve safety. And in order to do that, we need to be able to evaluate and assess things in a centralized, very organized manner.

So through the audits and reports Neal R. Gross & Co., Inc.

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Page 88 system, we'll be able to evaluate effectiveness to determine, just like in the FMEA, what are our opportunities to improve, and how do we make changes.

So change is anticipated, and actually desired, I think, to really take the big gamut and hone in to something that is more streamlined and more effective for the clinical end user.

MS. TOIGO: Mary? DR. WILLY: This is a question for

Dr. Chirieac. So you had a presentation that focused on some of the information you've collected in your study in this -- discussing risk/benefit. And I'm looking at your slide, and you said there are other types of information you're collecting.

And I'm interested if you could share with us maybe in our docket the information you've collected on the effectiveness of communication, and whether you've learned whether certain forms of


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Page 89 communication seem to be more effective, and also what you might have learned about access and burden.

DR. CHIRIEAC: Yes, the stakeholder project collected several layers of information, and I outlined them in the slide, but we do have more information. So we would be happy to submit that to the docket.

MS. TOIGO: Any other questions? Adam, you were waiting patiently. I saw your hand there, but -- so we'll let Megan go, unless yours was a follow-on to Mary's?

MR. KROETSCH: No. MS. TOIGO: No, okay. So go ahead,

Megan. MS. MONCUR: Yes, my question is

for Douglas Monroe. And you made an interesting distinction in your presentation, and you said, REMS do not fragment care, limited distribution does. And I apologize. I'm paraphrasing. But I'd like to hear a little bit more about that.


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Page 90 And also, this is kind of a

follow-on to that question, we try to write our REMS where it's a list of requirements so that, you know, if you meet the requirements or exceed the requirements, you can participate. But there still is a gap. And so if you can help us understand what that gap is, as well.

MR. MONROE: It's probably good to specify that there are drugs with limited or restricted distribution without REMS, as well those with REMS. Some of those without REMS have minor safety issues, some have larger safety issues, and then there's REMS drugs.

With a lot of the REMS drugs that have limited distribution, they might be contracted to be dispensed only by a few specialty pharmacies who do a very good job of meeting REMS requirements. But the part that was troubling to us is that it pulls it out of our system.

It's not available to all the Neal R. Gross & Co., Inc.

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Page 91 providers in

meeting transcript (7/26/13) (pdf - 3.4mb)

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