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Bluebook 21st ed.

Andrew Wilson & Christopher-Paul Milne, FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist, 66
FOOD & DRUG L.J. 569 (2011).

ALWD 6th ed.

Wilson, A.; Milne, C. ., Fda's risk evaluation and mitigation strategies (rems):
Effective and efficient safety tools or process poltergeist, 66(4) Food & Drug L.J.
569 (2011).

APA 7th ed.

Wilson, A., & Milne, C. (2011). Fda's risk evaluation and mitigation strategies
(rems): Effective and efficient safety tools or process poltergeist. Food and Drug
Law Journal, 66(4), 569-586.

Chicago 17th ed.

Andrew Wilson; Christopher-Paul Milne, "FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist," Food
and Drug Law Journal 66, no. 4 (2011): 569-586

McGill Guide 9th ed.

Andrew Wilson & Christopher-Paul Milne, "FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist"
(2011) 66:4 Food & Drug LJ 569.

AGLC 4th ed.

Andrew Wilson and Christopher-Paul Milne, 'FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist'
(2011) 66(4) Food and Drug Law Journal 569.

MLA 8th ed.

Wilson, Andrew, and Christopher-Paul Milne. "FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist." Food
and Drug Law Journal, vol. 66, no. 4, 2011, p. 569-586. HeinOnline.

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Andrew Wilson and Christopher-Paul Milne, 'FDA's Risk Evaluation and Mitigation
Strategies (REMS): Effective and Efficient Safety Tools or Process Poltergeist'
(2011) 66 Food & Drug LJ 569

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FDA's Risk Evaluation and Mitigation Strategies (REMS):
Effective and Efficient Safety Tools or Process Poltergeist?

ANDREW WILSON
CHRISTOPHER-PAUL MILNE

INTRODUCTION

The FDA Amendments Act (FDAAA) signed into law in 2007 granted the U.S.
Food and Drug Administration (FDA) broad new authorities related to the safety
of new and already approved drugs.' These included the power to require use of
Risk Evaluation and Mitigation Strategies (REMS) for new and already-marketed
drugs to ensure the benefits of certain drugs outweigh their risks. Although many
of the elements included under REMS had been utilized as part of earlier risk
minimization efforts, specifically Risk Minimization Action Plans (RiskMAPs),
the REMS provisions contained in FDAAA greatly strengthened FDA's hand
in managing post-market safety issues because for the first time it granted FDA
legal authority to require and enforce the use of such tools.' 3 Implementation of
REMS began in March 2008 and the initial list of products requiring a REMS
was composed of 16 drugs with existing RiskMAPS that were approved prior to
enactment of FDAAA; these were "deemed" to have an approved REMS. In the
nearly three years since that time, the number of required REMS has increased
precipitously; almost half of all New Molecular Entities (NMEs) and nearly 40%
of all New Drug Applications (NDAs) (i.e., NMEs plus new doses and formulations
of drugs) approved by FDA are required to have a REMS. 4 As of mid-June, 2011,
approximately 190 REMS programs had been approved by FDA.'
As the REMS program expands in number and nature, there has been an
increasing chorus of stakeholders who have expressed a range of concerns and
criticisms about the program's implementation. Taken as a whole, these groups

Mr. Wilson was a Senior Research Analyst at the Tufts Center for the Study of Drug Develop-
ment, Tufts University Medical School, Boston, MA. He is currently a Ph.D. candidate at the Heller
School for Social Policy and Management at Brandeis University.
" Dr. Milne is Associate Director of the Tufts Center for the Study of Drug Development, Tufts
University Medical School, Boston, MA. Financial Disclosure: This study was funded in part by a
grant from The Pharmaceutical Research and Manufacturers of America. Tufts Center for the Study
of Drug Development is funded in part by unrestricted grants from sponsors in the biopharmaceutical
sector and related industries. The authors have no other relevant affiliations or financial involvements
to report.
' Food and Drug Administration Amendments Act of 2007, Pub. L. No. 110-85, § 901 (codified
at 21 U.S.C. §355-1 (2007)). This Act, known commonly as FDAAA, is also the fourth iteration of the
Prescription Drug User Fee Act, known as PDUFA IV, which will sunset on September 30, 2012.
2 Laura B Faden, Christopher-Paul Milne, Pharmacovigilanceactivities in the United States,

European Union and Japan: Harmonic convergence or convergent evolution? 63 FOOD & DRUG LAW
J. 683 (2008).
3 Deborah B.Leiderman, Riskmanagementofdrugproductsand the U. Food and DrugAdministra-
tion: Evolution and context. lO5S Drug Alcohol & Dependence S9-S 13 (2009).
4Michael McCaughan, REMS 2.0: FDA refining new drug safety tools. 4 THE RPM REPORT

(Nov 2010), available at http://sis.windhover.com/buylabstract.php?id= 20 105001 31.

Food and Drug Administration, Approved Risk Evaluation and Mitigation Strategies (REMS),
[REMS website] available at http://www fda.gov/Drugs/DrugSafetylPostmarketDrugSafetylnforma-
tionforPatientsandProviderslucml Ill 350.htm

569
570 FoOD AND DRUG LAW JOURNAL VOL. 66

have indicated REMS is having a significant impact on the health care system.
Yet, over three years into implementation the nature and depth of this impact
among these groups remains largely unknown as much of the knowledge about
these effects remains disparate and anecdotal. Given that the number of products
with REMS is anticipated to expand, the impact will only become broader and
more profound in the coming years. There is, therefore, a need to understand these
issues ina more systematic way. In this paper, the authors sought to examine the
collective concerns and experiences of a diverse set of stakeholders about REMS
program implementation and its impact on the health care delivery system. This
paper presents the findings of that work.
Section one begins by describing the various REMS program requirements and
components as outlined in FDAAA. Section two describes the methods used to
interview individuals representing different groups, who are REMS stakeholders
(and includes a brief mention of a subsequent follow-up survey of the interviewees
published elsewhere). Results are presented in section three, with a discussion of
the findings in section four, followed by a conclusion.

I. BACKGROUND

A. FDAAA: REMS Provisionst

Section 505-1 of FDAAA granted the FDA authority to require a REMS as
part of a pending application for product approval or for an already approved ap-
plication if a determination is made that one is needed to ensure the benefits of the
drug outweigh the risks. For drugs seeking approval, FDA makes its determinations
based on multiple factors: estimated size of the population that will use the drug,
seriousness of the disease being treated, expected benefit of the treatment, duration
of treatment, the seriousness of associated known or potential adverse events and
whether the drug is a new molecular entity. Determinations about drugs currently
on the market are made when the FDA becomes of aware of new safety informa-
tion about a serious or unexpected risk related to use of the drug through a clinical
trial, adverse event report, post-approval study, or other scientific data. The FDA
can request a REMS for any pending or approved New Drug Application (NDA),
Abbreviated NDA (ANDA), or Biologic License Application (BLA). Applicants
are individually responsible for the development, implementation, assessment, and
modification of a REMS.
Table I lists the specific components that are included in REMS as they are
detailed in FDAAA. The law mandates that all REMS include a series of as-
sessments at predetermined intervals of 18 months, three years, and seven years
following initial plan approval, however the FDA has in a few instances requested
initial assessments be completed in as soon as six months. In addition, REMS may
include one or more of the following components: medication guides [hereinafter
MedGuides], communication plans, and/or elements to assure safe use [hereinafter
ETASU]. Medication guides are handouts used to inform patients about the safe

6 See FDA Guidancefor Industry: Formatand Content of ProposedRisk Evaluation and Mitigation
Strategies (REMS), REMS Assessments, and ProposedREMS Modifications (Draft Guidance, September
2009), availableat http://www.fda.gov/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/
default.htm. Although the FDA issued draft guidance on REMS in September 2009 outlining the require-
ments in more detail, the public comment period remains ongoing.
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 571

and effective use of a drug in order to help them avoid serious adverse events.7
Communication plans utilize various methods of dissemination (e.g., direct mail-
ings, communications via professional societies, etc.) to communicate risk and
REMS-related information to health care providers.
According to FDAAA, ETASU are reserved for drugs associated with a serious risk
of adverse drug experiences that would otherwise be denied approval or withdrawn.8
ETASU are comprised of a set of tools that enable the applicant to monitor, evaluate,
and improve implementation (Table 1). When a determination is made that they are
needed, FDAAA is not prescriptive about what ETASU should be utilized or how
they should be designed; nor does it grant FDA this authority. Rather, the law only
specifies that inclusion of ETASU be "commensurate with the serious risk listed in
the labeling of the drug."' FDAAA further attempts to prevent ETASU from being
overly restrictive by requiring that they minimize the burdens on patient access and
the overall the health care system by conforming to existing ETASU for drugs with
a similar risk or be designed in a way that fits with existing distribution systems. In
this respect, the law attempts to strike a balance between the need for heightened
safety monitoring and impediments on the delivery of care by giving drug sponsors
leeway to develop ETASU according to specific circumstances.

Table 1: Components of Risk Evaluation & Mitigation Strategies Outlined in

FDA Guidance

A. "Minimal Strategy" J C. Elements to Assure Safe Use

All REMS must include a timetable May include one or more of the
for assessment at defined intervals: following:
* 18 months Special training and/or certification
* 3 years requirements for prescribersor
* 7 years dispensers of the drug;
Restricting distribution of the drug
to particular care settings;
B. "Additional Potential Elements" Dispensing a drug based on evidence
REMS may include: or documentation of safe use
Medication guides and/or conditions (e.g., patient counseling
patient package inserts and acknowledgement of risks and
Communication plans benefits, informed consent);
" Patient monitoring and follow-up
(e.g., periodic lab testing);
" Use of patient registries.

Sponsors may also develop

implementation systems with which
to monitor, evaluate, and improve
implementation of ETASU elements.

See FDA Website, Medication Guides, available at: http://www.fda.gov/Drugs/DrugSafety/Post-

marketDrugSafetylnformationforPatientsandProviders/ucm l 11350.htm. Accessed: Feb. 18, 2011.
FDAAA,Sec. 505-l(b)(4). FDAAA defines a "serious adverse drug experience" as any adverse event
that results in death, immediate risk of death, hospitalization or extension of hospitalization, incapacity or
disruption of normal life functions, a congenital anomaly or birth defect.
9 FDAAA Sec. 505-1 (0(2) (A).
10 FDA Draft Guidance (2009), supra note 6.
572 FOOD AND DRUG LAW JOURNAL VOL. 66

H. METHODS

The authors' investigation was conducted in two phases. The first phase consisted
of a series of qualitative interviews with individuals representing the experiences
and opinions of five stakeholder groups involved in various aspects of REMS
programs. The groups were comprised of representatives of biopharmaceutical
companies, payers, health care providers (HCPs), pharmacists, and patient advocacy
organizations. Initially, potential respondents were selected if they were individuals
with direct involvement in the design, implementation and/or assessment of REMS
programs for drugs or diseases (e.g., ESAs, opioids and orphan drugs) that tended to
have more complicated REMS (i.e., not just MedGuides, but also a Communication
Plan and/or ETASU) and in the case of particular drugs, an assessment was due.
Later, participation was expanded to individuals who were knowledgeable about
the particular experiences of their constituencies in dealing with REMS, or who
worked on REMS in some broad capacity, such as contract research organizations
(CROs) acting as regulatory consultants. Individuals were identified by means of:
information available in the public domain, such as attendee lists of professional
conferences and FDA public meetings; articles in the peer-reviewed and trade litera-
ture; submissions to the FDA public docket (e.g., letters to the FDA Commissioner
from various professional associations); and referrals from other interviewees and
organization contacts (e.g., The Pharmaceutical Research and Manufacturers of
America, National Organization of Rare Diseases, etc.).
Respondents were from a diversity of constituencies and backgrounds. The
group of health care providers was comprised primarily of physicians from many
different perspectives and care settings, including professional medical societies,
hospice care, dialysis clinics, specialty care and health care businesses. Drug spon-
sor representatives included individuals from large and small companies, as well as
CROs, which had been involved with REMS programs for multiple sponsors. The
drug sponsor respondents held variousjob titles (e.g., CEO of a small biotech firm,
vice-president of Global Safety and Risk Management, REMS Manager) and had
various backgrounds (e.g., regulatory affairs, medicine, pharmacy and business).
Respondents from patient advocacy groups were from disease-specific organiza-
tions and national organizations covering broader patient issues. Payers included
individuals from both traditional insurers and pharmacy benefit managers whose
experience with REMS was either indirect through interacting with pharmacies and
drug sponsors and developing organizational support services, or direct through
ensuring that in-house mail-order and specialty pharmacy services are in compli-
ance with REMS programs. Lastly, the pharmacist cohort included a diverse group
comprised of practicing pharmacists, hospital clinical pharmacists, employees of
pharmacy services companies and representatives of national pharmacy organiza-
tions spanning multiple pharmacy settings (e.g., retail, specialty, and hospital).
Each interview was conducted using a standard format questionnaire followed
by one or more directed questions tailored to each stakeholder group. In general,
the questionnaire was assembled from information extracted from a variety of
publicly available sources, such as: FDA Guidance for Industry; the FDA Public
Docket; trade literature; professional journals; and, personal communications with
colleagues, who had piloted a draft version of the interview guide. Questions were
organized around the following themes:
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 573

* REMS implementation and administration;

* REMS components (i.e., MedGuides, communication plans, certain ETASU-
restricted distribution schemes, laboratory testing, informed consent, and
patient registries);
* Effects on patient access and delivery of care;
* REMS program outcomes;
* Issues specific to each stakeholder group.

The majority of interviews were conducted over the phone between June and
October 2010. Two were conducted in-person at public meetings. In total, 47 inter-
views were completed. The number of respondents from each stakeholder group
was as follows: Drug Sponsors - 13 (including 2 CROs); Pharmacists - 11; HCPs
- 11; Patient Advocates - 8; and Payers - 4.
Following the interviews, a brief survey instrument was derived from common
themes cited in the interviews as well as continued assessment of information in
the public domain. Its purpose was to gather quantitative categorical data about
the collective experience with REMS across stakeholders. All 47 interviewees were
contacted about the survey and individual responses were collected electronically
via the web-based survey tool, Survey Monkey. In total, 28 interviewees provided
responses, giving a response rate of 60%. Responses from each cohort were as fol-
lows: Patient Advocates - 3; Drug Sponsors - 8; HCPs - 7; Payers - 2; Pharmacists
- 8. These results have been reported elsewhere."

I. RESULTS

Providing results of interviews with nearly 50 stakeholders from five different

perspectives on the implementation of a new regulatory scheme with multiple
components and manifold complexities is by definition challenging. We have at-
tempted to represent respondent views as faithfully as possible within the limits of
the compilation process as well as the necessary confines of the reporting process
itself in the interests of brevity and comprehensibility. There was a natural tendency
for respondents from one stakeholder group to comment on what they believed
other stakeholder groups were experiencing or thinking about particular issues.
To the extent possible, when such responses were not accompanied by evidentiary
support or seemed to be widely and repeatedly voiced by many respondents, we
excluded such remarks. Descriptions of some vignettes, whether related vicariously
or first-hand, however, were too illustrative to be excluded without losing some of
the tenor of the collective experience, especially with regard to apparently unan-
ticipated consequences and complications. The authors attempted to identify such
accounts as anecdotal, when sources and circumstances so indicated.

A. Administrative, logistical & workflow burdens ofREMS.

Implementation
Most respondents agreed generally that record keeping systems for tracking
REMS-related data and materials, monitoring participant eligibility, education and
outreach activities require extra work and/or staff and took time away from other

"See generally Kaitin KI (ed.), US healthcarestakeholders uncertain on benefits of risk evaluation

strategy (Jan/Feb 2011), Tufts Center for the Study of Drug Development Impact Report.
574 FOOD AND DRUG LAW JOURNAL VOL. 66

duties, especially for REMS with ETASU. They also generally agreed that more
standardization of REMS requirements, tools and protocols could alleviate some
of the burden. Cohort-specific examples of additional concerns were as follows:

1. Health care providers

REMS are being applied too broadly. For example, REMS for erythropoietin
stimulating agents (ESAs), which are intended to reduce the risks of decreased sur-
vival or poorer tumor outcomes for cancer patients on ESAs, are also being applied
when ESAs are used in the treatment of end-stage renal disease, even though the
risk is not the same for that indication. As a result, many patients, even in moni-
tored clinical settings, such as dialysis units, are being unnecessarily subjected to
the same rigorous REMS requirements.

2. Drug sponsors
Like health care providers, drug sponsors were also concerned about the incon-
sistency and rigidity of REMS requirements. At particular issue for drug sponsors
was the difficulty of obtaining the voluntary compliance of pharmacists and health
care providers for REMS programs.

3. Patient advocates
While patient advocates thought REMS have been an added burden on the health
care system, some viewed the larger challenge to successful implementation to be
the creation of "behavior change."

4. Payers
Payers agreed that the implementation of REMS have created significant burdens,
which ultimately translate into added costs that are passed on to patients.

5. Pharmacists
Several interviewees cited problems adjusting to the requirements of a REMS
program for marketed drugs that did not previously have one. In the case of one
regional pharmacy chain, for example, the confusion about the launch of various
REMS programs for these drugs had become so great the company created a special
website to address staff questions about the different processes involved.
Because each REMS program follows its own administrative processes, phar-
macists have often had to maintain multiple sets of records that exist separately
from their normal systems, creating considerable redundancy and complexity. This
has also challenged organizations that have attempted to adapt some of these pro-
cesses to their specific needs. For example, one respondent described the difficulty
her organization had faced integrating REMS processes between its inpatient and
outpatient practice settings.

B. Effects of RtEMS on PatientAccess and Delivery of Care

2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 575

Respondents were queried about the impact of REMS implementation on patient

access and delivery of care from factors previously identified in the public debate
as being of concern such as: overall program burden; uncompensated time spent by
HCPs and pharmacists; limiting the number of distributing pharmacies; logistical
roadblocks; and the security of patients' private medical information.

1. Health care providers

More than half of respondents believed the additional burdens imposed by
REMS deter health care providers from participating in programs. This was believed
to be especially true for physicians in small family practices, but less so among HCPs
practicing in large multi-practitioner medical groups. A slightly larger number of
respondents further believed that restricting the number of pharmacies allowed to
distribute a drug ultimately limits patient access.

2. Drug sponsors
More than two-thirds of the respondents thought that REMS programs limit
patient access. There was general agreement that limiting pharmacy distribution
also restricts access to the drug.

3. Patient advocates
Patient advocates believed there were a number of logistical obstacles created
by REMS that have restricted access for patients, such as provider availability or
the fragmentation of care across different providers. For example, one respondent
noted that if the number of physicians participating in a program is limited, a
scarcity of available providers could place them too far away for patients who are
unable to travel or cannot afford the costs. On the other hand, another respondent
did note that it may be hard to separate the effects of REMS from more traditional
factors usually associated with limiting patient access.

4. Payers
None of the payers interviewed thought the burdens of REMS had discouraged
pharmacists from participating, though they did feel that the further expansion in
the number of drugs subject to REMS programs could change that. Unlike other
groups, however, they did not view restricting the distribution of drugs as a limita-
tion on patient access because distribution of the drugs in which these schemes are
required tends to be limited anyway.

5. Pharmacists
Pharmacists saw REMS as limiting patient access in a general sense, though
none believed that REMS had been identified as a specific deterrent on phar-
macist enrollment in programs. Most concerning among this group has been the
fragmentation of care resulting from limiting the type of pharmacy or health care
settings that are allowed to dispense some REMS drugs through restrictive distri-
bution schemes. In the community pharmacy, for instance, it was felt that use of
mail-order or specialty pharmacies by REMS programs have removed pharmacists
576 FOOD AND DRUG LAW JOURNAL VOL. 66

from the dispensing process. The belief was that this has disrupted patient care
because patients no longer have an easily accessible health care professional they
can routinely rely on to explain important prescription-related information. Also,
there have been instances of patients being cut off from their regular prescriptions
while hospitalized when those drugs were exclusively restricted to distribution by
specialty pharmacies as part of a REMS program.

C. REMS Tools and Components

Responses varied among the stakeholder groups in terms of focus and satisfac-
tion with particular "tools." Of the REMS on the most recent FDA listing, nearly
160 detailed the tools included in the program (with the exception of sponsor
programs that had already fulfilled their REMS requirements sufficiently such
that their status was listed as "released"). Some 96% of REMS had MedGuides,
33% had communication plans, and only 17% had ETASU.12 Table 2 provides an
aggregated summary of stakeholder comments for each REMS component, but
notable concerns and examples voiced by stakeholder group are discussed below.

1. Health careproviders
In general, interviewees representing health care providers stated that their
members are typically not concerned with MedGuides unless the REMS requires
that these materials be distributed in the practice setting. Where used, however,
they were viewed by respondents as burdensome and ineffective. In dialysis clinics,
for example, one respondent mentioned that half of their patients are unable to
read MedGuides due to vision, language, and literacy problems. It was also stated
that MedGuide information is weighted too much toward risk, and serves more
as a tool to limit the liability of sponsor companies than a resource for patients.
The health care provider cohort generally expressed similar views about materi-
als received through communication plans, i.e., that they don't balance risk and
benefit information and are generally ignored by physicians. It was suggested that
information about REMS could be more effectively disseminated through channels
of communication already established to distribute prescribing information, such
as those used by professional medical societies.
Most were supportive of the use of laboratory testing as a pre-condition for
receiving a drug since it is used by physicians routinely anyway. Nonetheless, it was
observed that better administrative processes around these requirements would
help. While there was some limited support for REMS tools generally, added costs,
compliance, and privacy of patient information were real concerns for them.

2. Drug sponsors
Qualified support was expressed for most REMS tools. Drug sponsors were es-
pecially critical of MedGuides, which they believed were ineffective and should not
be included as part of REMS. Several were also frustrated by the burden of what
they called a "knock-on" effect in which changes to the prescribing information of a
REMS drug causes a change to the MedGuide, which then requires a formal change
to the REMS plan.
While half thought communication plans were useful, several were skeptical that
providers actually read the materials sent to them. Indeed, in a survey conducted by
12 FDA REMS website. supra note 5.
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 577

one respondent's organization, just 4 of 250 physicians indicated they had read the
Dear Health Care Provider letter sent to them.
Most respondents thought the 18-month timeframe for the initial REMS as-
sessment was reasonable, but felt REMS that include an initial assessment at six
months was too short a time frame to collect good data. Furthermore, in terms of
the assessments themselves, it was not clear to drug sponsors how the results should
be interpreted because information about the FDA's expectations has been lacking.
On one hand, drug sponsors have been uncertain about what constitutes "success"
of the REMS, while on the other hand, some are doubtful certain elements could
be adequately assessed in the first place. As one respondent put it: "Confirmation of
comprehension in what proportion of patients receiving MedGuides makes it effec-
tive? Is it 60%? 80%? Who knows?" Another asked rhetorically, "How do sponsors
properly assess whether restrictive distribution schemes have successfully prevented
the 'wrong' patients from receiving the drug and what is an acceptable level?"

3. Patient advocates
Patient advocates supported the need for registries if for nothing else than to
gain access to a drug that would be unavailable without one. However, they did join
health care providers in concerns over the privacy of patient's health information, but
thought that the level of concern did not trump the need to collect the information,
and that there were safeguards in the system.
The greatest concerns for this group of respondents were MedGuides and informed
consent forms, both of which were viewed negatively because they are skewed too
heavily toward describing risks and included too much irrelevant (and sometimes
conflicting) information for patients. With respect to MedGuides, patient advocates
considered them to have too much information and too little of it was on benefits.
In any case, many said, such information should be coming to the patient from their
HCPs. They also concurred with HCPs' view that MedGuides appear to be designed
as a tool to limit the liability of drug sponsors. Informed consent forms were seen as
too difficult to understand because the information contained in them is overly broad
and does not apply to the particular situations of individual patients.
Lastly, respondents took issue with obligatory lab testing because many thought
it just added an extra logistical hurdle for patients and extra cost to the health care
system, which were unnecessary in certain circumstances. One further questioned the
wisdom of having decisions about such requirements made by FDA, rather than the
patient's health care provider.

4. Payers

There was general support by respondents for communication plans. Laboratory

testing was also seen as necessary in some situations, although it was suggested it can
be a burden and is sometimes overused. With regard to restricted distribution schemes,
payers thought they should be reserved for drugs with small, targeted populations.

5. Pharmacists
While not necessarily opposed to requirements for lab testing in REMS programs,
pharmacists noted several concerns about the verification process. First, confirm-
ing the completion of tests or monitoring results is time-consuming because the
information is not usually provided by the patient's physician or the labs to the
 578 FOOD AND DRUG LAW JOURNAL VOL. 66

pharmacists. Because of this, additional follow-up with physician offices is required

to obtain confirmation, and sometimes pharmacists must rely on confirmation
directly from patients. Second, testing requirements have sometimes been applied
too broadly. The common example cited was the drug bosentan (Tracleer) and
the risk of fetal exposure. Because the REMS program requires confirmation of
a negative pregnancy for any female patient receiving the drug, some groups (i.e.,
children and the elderly) are subjected to unnecessary testing.

Table 2: Summary of stakeholder comments on REMS tools**

I
Too long and contain excessive and inapplicable information
(DS,PA,Ph)
Do not properly balance risk and benefit information (HPDS,Ph)
Designed for liability protection rather than informational
Medication
purposes (HPPA)
Guides
Lack input from health care professionals and patients (HPPA)
Information may not be applicable to all populations receiving the
drug (e.g., pediatrics) (HP)
Can be useful, but need improvement overall (DS,Ph)
Materials do not properly balance risk and benefit information
(HP)
.c Information is usually ignored when it is from drug sponsors
Communication(HPDSPh)
Do not change physician behavior by themselves (HPPA)
Information better distributed through existing communication
channels (e.g., professional societies) (HPPA,Ph)
ETASU
Have been restrictive/burdensome; created delays in patient access
Restricted (HP, DS, Ph)
distribution Have helped to effectively regulate access and/or improve safety
schemes(DS)
Have removed some pharmacists from the dispensing process (Ph)
Should be used sparingly or as a last resort (DS,Ph)
Have been useful (often done routinely anyway), but need better
administrative processes (HPDS)
Have resulted in better data (DS)
Costly, unnecessary, and compliance is poor (PA)
Lab testing Decision to test should be made by a patient's physician, not drug
sponsors or FDA (PA)
Necessary in some situations, though sometimes overused (PY)
Verification of test completion is difficult and time consuming
(Ph)

Added burden to patients and physicians (HPDS)

Informed Can be useful in educating patients about risk (HP)
consentlPatient Can include too much information in risk (DS)
agreement forms Impractical; too difficult to design one form that applies to all
patients (PA)
Best suited for unusual and/or serious risks (PY)

continued
 2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 579

Concerns about privacy of patient information and patient

stigmatization attached to the use of certain drugs (e.g., opioids)
(HP,PA,Ph)
Useful, though added burdens, costs passed on to patients, and
Patient non-compliance are problematic (DS,PY)
registries Involvement of patient organizations in registries could make data
collection more effective (PA)
Helpful to drug sponsors for identifying patient population taking
the drug, as well as ensuring patients are educated and outcomes
are measured (PYPh)

Basic timeline is reasonable (DS,Ph)

Concerns about whether 18-month initial assessment not enough
time to collect useful data; ongoing enrollment and compliance
Tinelimntof issues with REMS programs for facilities could make assessments
difficult. (HPDS,PA,Ph)
There is a lack of guidance about what FDA wants included in
assessments (DS,PA)

**Abbreviations: HP=Health care providers; DS=Drug sponsors; PA=Patient advo-

cates; PY=Payers; Ph=Pharmacists

D. REMS Program Outcomes

In this section, respondents were questioned about whether REMS had made
the situation better or worse compared to the impact of previous risk management
programs; whether-REMS had created unintended consequences such as shifts in
prescribing patterns, accessing medicines outside legitimate channels, or improper
substitution of non-REMS drugs for prescribed REMS drugs; and whether there
were other unanticipated consequences, positive or negative.

1. Health care providers

The majority indicated they believed the burdens of REMS are the same or
worse as before. Moreover, two respondents indicated they had observed shifts
in prescribing away from use of ESAs. About half the providers viewed shifts in
prescribing as something that is likely to continue to occur. Nearly all those inter-
viewed also believed drugs are being improperly substituted. The example that one
respondent mentioned was anecdotal instances of substitution of non-REMS pain
drugs, such as Tylenlol III, for Onsolis in order to avoid having to comply with the
REMS requirements.
On a positive note, HCP representatives have acknowledged that REMS have
compelled them to some degree to take more time for patient-doctor communica-
tion.
On the negative side, there were instances when patients given MedGuides were
"scared'' by the information to such a degree that they balked at being administered
the prescribed drug. In fact, one respondent described an incident where a number
of patients in a dialysis unit, who received their MedGuides more or less at the
same time, proceeded to discuss the MedGuide information amongst themselves.
580 FOOD AND DRUG LAW JOURNAL VOL. 66

These patients became so concerned about the risks that they rebelled against tak-
ing their drugs for almost a week.

2. Drug sponsors
Nearly 80% stated that REMS have made the burdens on the health care system
worse. Several respondents had experienced pushback from physicians and hospitals
about taking on REMS tasks. Specifically, enrollment and certification programs
are being viewed by providers as shifting liability away from the drug sponsors.
Among hospitals, registries are viewed as an instrument to collect medical data
for scientific purposes, something they are typically compensated for. However,
hospitals are not compensated for registries created through a REMS program.
Another outcome of REMS has been the increase in a drug's price to compensate
for the administrative costs of the program. In the case of one sponsor, who set up
a company specifically to provide an orphan drug to just a few hundred patients, it
resulted in a 4-fold increase in the price charged to patients for the drug.
In terms of positive, unanticipated consequences, some drug sponsors note that
they have provided sponsors the opportunity to collect better safety and other
important patient-related information. On the negative side, there is the potential
for sponsors of products with REMS to experience a marketing disadvantages
against competitors with therapeutically similar products that don't require REMS.

3. Patientadvocates
All respondents thought the burdens created by REMS have made things worse.
Respondents also agreed that there have been shifts in prescribing patterns with
patients sometimes choosing to go off medicines all together, except in the case
of orphan drugs where there are few, if any, alternatives available on the market.
On the negative side, it was generally believed that the time burden of REMS
compliance for physicians and pharmacists has been far greater than was initially
anticipated.

4. Payers
As for unanticipated consequences, on the positive side, the payers view slower
uptake and shifts in prescribing patterns related to REMS drugs as not unintended
or unwelcome outcomes from the program. On the negative side, payers expressed
concern that REMS are being improperly ascribed blame for pre-existing problems
with access.

5. Pharmacists
Nearly all viewed the burdens of REMS as the same or worse than earlier pro-
grams, but not better. Several pharmacists believed there has definitely been a shift
in prescribing away from REMS drugs, particularly for the ESAs and certain pain
drugs - fentanyl buccal (Onsolis) and vigabatrin (Sabril). Others thought that this
is only theoretically possible or it is too early to tell.
As far as positive consequences, there was the opinion that, despite the added
burdens, REMS have been a step toward improving patient safety by increasing
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 581

education and awareness overall of drug safety and risk. On the negative side, there
were others who believed that failure to account accurately for the impact of REMS
implementation has led to decreased patient access, increased costs, and significant
burdens on the working environments of pharmacists.

E. Stakeholder-specicquestion and comments

In this final section, each stakeholder group was asked questions that background
research indicated may be of particular concern to their constituencies. In addition,
respondents were given an opportunity to provide comments related to important
points that had not been discussed or that they wished to highlight.

1. Health care providers

Health care providers were asked whether there have been times when the
implementation of REMS has been an intrusion on the practice of medicine. The
general response was that there had been times when REMS had been an intru-
sion on medical practice, or at least, had made practicing medicine more difficult.
In comments, some in the HCP group noted that few of their members had ac-
tually expressed much interest or opinions about REMS (except perhaps for those
prescribing opioids). Nonetheless, respondents believed that they should be more
involved with the REMS programs while they are still in development by FDA.

2. Drugsponsors (CRO responses were not included)

a. How have drug approvaland or launch been affected

by REMS?
Seven of 11 respondents indicated REMS have delayed final FDA approval by
as much as 3-6 months. In particular, drug sponsors were frustrated that the FDA
was engaging with them about REMS too late in the approval process, so they
could not sufficiently plan for post-approval activities.

b. Has your organization hired new staff or created a

new office or department as a result of REMS?
Nine of 11 sponsors had already hired or were planning to hire additional staff.
Of those, two respondents had reorganized internal departments and existing staff,
while another one has created an entirely new department to meet the administra-
tive demands of REMS.

c. On a scalefrom 1 (negligible burden) to 5 (very

signficant burden), what has been the additional
burden of creating and implementing REMS programs
in terms of time, money, staffing, practicaland legal
obstacles?
Two respondents provided a score of 5; five gave a rating of 4; and, two rated it
a 3. The remaining two respondents provided more nuanced answers, each rating
REMS with ETASUI a 5, but REMS with a MedGuide and/or communication
plan only a 3 and 4, respectively.
582 FOOD AND DRUG LAW JOURNAL VOL. 66

In comments, several in the sponsor cohort expressed the concern that REMS
were disrupting business relationships (e.g., un-leveling the playing field for thera-
peutically similar drugs with and without REMS) and contracting arrangements
(e.g., no longer paying hospitals for data that they had formerly been paid to col-
lect), as well as by creating new business risks (e.g., shifting liability for informing
patients of safety risks from drug companies to persons outside their control).

3. Patient advocates
Patient advocates were questioned about potentially better alternatives to patient
education than informed consent/patient agreement forms, which are seen as inef-
fective. Most agreed with the idea that such forms are ineffective as they are used
more for liability protection and don't provide enough balance between risks and
benefits. It was also felt that time spent by health care providers and pharmacists
educating patients should be reimbursed or that other alternative reimbursement
mechanisms should be explored that would include incentives for patient education.
In comments, patient advocates generally felt that while it was most appropriate
for risk/benefit information to be communicated to patients by their HCPs, the
lack of compensation of HCPs for the extra time and resources threatened patient
access. Similar to the HCP respondents, patient advocates were not hearing a lot
about REMS directly from their constituents. Advocates generally expressed the
view that sufficient safeguards were in place to protect patient privacy even with
the additional data being collected though REMS programs.

4. Payers
The question posed to payers asked whether problems with multiple fragmented
systems of health information technology in pharmacy and medical practices
contribute to non-compliance of REMS requirements. They responded generally
that while health information technology systems may be in place, a general lack
of integration and coordination between providers means that critical information
is not being communicated. This, in their view, makes such systems often no better
than paper.
In comments, payers on the one hand expressed the belief that MedGuide type
information was best delivered in the context of a patient-doctor conversation,
while on the other hand noted that whatever extra resources that were required of
them would result in pass-along costs.

5. Pharmacists
Pharmacists were asked whether they had experienced problems with REMS
implementation due to the vagaries of pharmacist working environments (e.g.,
working in multiple locations, various operating systems, etc.). Ten of the eleven
respondents indicated they were aware of problems, however, these had generally
been described in earlier responses.
In comments, pharmacists viewed the increased awareness of safety and extra ef-
forts devoted to patient education generally as a good thing except that it often came
at the expense of the time and resources they had to perform their routine duties.
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGEs 5
583

IV. DISCUSSION

What was most surprising was not that respondent groups with such divergent
perspectives and diverse roles within the REMS program disagreed on certain
points, but rather that they agreed on so many points. For example, there was gen-
eral agreement that the program is burdensome and not an improvement over the
previous program of RiskMAPS. Respondents also concurred almost unanimously,
regardless of their role, that the patient information is weighted much too heavily
on the risk end of the risk/benefit scale. Similarly, there was general concern from
all the responder groups about uncompensated time and resources expended by
HCPs and pharmacists and the impact this might have on their participation in the
program, especially as REMS program begin to encompass a greater proportion
of drugs. The latter was also a concern with regard to increasing the impediments
to patient access to REMS drugs.
Also surprising was the fact that although many respondents were selected
based on association with more complicated REMS (i.e., those with requirements
beyond just a MedGuide program), the most fundamental and basic of REMS
tools, the MedGuide, remains a source of a significant amount of criticism. In fact,
our findings confirm problems with MedGuides identified in some early assess-
ments of REMS programs. For example, an evaluation of eight REMS programs
conducted by the consulting group, United BioSource Corporation, found that
while an average of 83% of patients had received the MedGuide, only 70% had
actually read it, and just 63% indicated they understood the key risk messages.'3
Moreover, as our investigation uncovered particular problems for specific patient
cohorts such as dialysis patients, so too, did the United BioSource Corporation
data show that comprehension may be heavily dependent upon the characteristics
of the intended patient population as schizophrenic patients demonstrated the
lowest comprehension.14
Communication plans were not far behind in the degree of disdain with which
they were viewed, mostly on the basis they were ineffective and not well thought
out. In the previously cited consulting group study, an average of 74% of health
care professionals understood the key risk messages of the communication plans,
while the ideal target number is "well over 80%."
Opinions on ETASUs from our interviewees were more variable, ranging from
some who said such measures were already de rigueurfor many high-risk drugs to a
few who said that these additional procedures had rendered the drug almost unmar-
ketable. There was consensus, however, that if ETASU became the norm rather than
the exception, this would be difficult to manage throughout the healthcare system.
On the to-be-expected side of the ledger, there was considerable agreement
regarding criticism of FDA on several counts: opportunity for stakeholder input
either was not sufficient or not timely enough; time and resource burdens of those
who actually had to implement the program had not been accurately predicted (or
taken into consideration); and, FDA had not provided enough guidance on what
data they wanted companies to collect in the assessments.
Positive aspects to REMS were mentioned by a number of respondents from
various grohtps. There was widespread recognition that the REMS program was
13 Sue Sutter, Early REMS assessments show room for improvement in medguides. THE PINK

SHEET (Nov. 29, 2010), (Vol.72, No. 48, Page 7).

'" Id.
584 FOOD AND DRUG LAW JOURNAL VOL. 66
the threshold through which a "risky" drug must pass to reach or remain on the
market. There was also near consensus that REMS have increased awareness and
attention on the need for better education and monitoring to improve drug safety.
Somewhat unexpectedly, there was praise for REMS from respondents in several
different groups about the benefit in terms of the opportunity for better data col-
lection. Speaking in the subjunctive, respondents believed that REMS may provide
better communication channels for information critical to patient care when the
program is fine-tuned and compliance is uniform.
Since the time when these interviews were conducted, some positive developments
are taking shape as the REMS program evolves in response to the public discourse.
New guidance calls for FDA to exercise enforcement discretion for MedGuide
distribution. MedGuides need not be distributed when a drug is dispensed under
certain conditions such as: to a health care professional for administration to a
patient in an inpatient setting; or, to a healthcare professional for administration
to a patient in an outpatient setting, such as in a clinic or dialysis or infusion center
and the like.' 6 FDA is further preparing for life "beyond REMS" by gearing up
a new program it refers to as failure modes and effects analysis that will help it to
evaluate potential safety problems early on with a process or product."
Nonetheless, PDUFA V negotiations are shaping up to be a REMS battleground
with lines of engagement already being drawn.'8 Among the issues in contention
are: whether to provide more specificity in REMS requirements or more authority
to FDA for specifying exact terms in REMS; the need to get REMS better aligned
with post-marketing commitments; and, the need to get the Office of New Drugs
and the Office for Surveillance and Epidemiology (both within the FDA's Center for
Drug Evaluation and Research) thinking along the same lines, or at least the same
timelines, in terms of REMS review and PDUFA performance goals.'9 Early "shots
across the bow" in the press would seem to indicate that allies and ambuscades on
the REMS front will be hard to see coming. On the one hand, several members
of an FDA Advisory Committee discussing the agency's proposal to manage the
risk of long-acting/extended release opioids said they were hesitant to support it
because of uncertainty about its success without a pilot program, a power which
FDA does not have. 20 On the other hand, another FDA advisory committee deci-
sion called for a company to develop a REMS even though FDA had not told the
company one was necessary, thus taking unto themselves a power that FDA does
actually have. 2 1 Similarly, the Infectious Disease Society of America, although gen-
erally supportive of incentives to lessen the entry burden for R&D of antibiotics,
has nevertheless called for the imposition of REMS-based restrictions to control
6 Guidancefor Industry. Medication Guides - Distribution Requirements and Inclusion in Risk
Evaluation and Mitigation Strategies (REMS). (Draft, February 2011), U.S. Department of Health and
Human Services, Food and Drug Administration, available at http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatorylnformation/Guidances/UCM244570.pdf
" Sue Sutter, CDER Eyes prioritization,Timely Resolution of Post-MarketingSafety Issues, THE
PINK SHEET (Nov. 29, 2010)., (Vol. 72, No. 48, Page 11).
18 PDUFA V will be the fifth iteration of the Prescription Drug User Fee Act, which was originally
enacted in 1992 and has been reauthorized every five years, with the expectation that it will be renewed
as PDUFA V and become governing law as of October 1, 2012.
'* Steve Usdin. PDUFA: A lot of Talk. BIOCENTURY: THE BERNSTEIN REPORT ON
BIOBUSINESS (June 6, 2011), available at http:l/www biocentury com/biotech-pharma-newscover-
story/20 11 -06-06details-on-fda-industry-deal-for-pdufa-v-its-about-meetings-not-money-al.
20 Cathy Dombrowski, The Limits of REMS: Opioid Debate Shows Shortcomings of New FDA
Powers. THE PINK SHEET (August 2, 2010). (Vol. 72, No. 31, Page 27).
21 CDER Eyes Prioritization, supra note 17, at 9.
2011 FDA's RISK EVALUATION AND MITIGATION STRATEGIES 585

antibiotic overuse.22 Even more inscrutable is that both sides seem to be hedging
their bets, FDA is frenetically trying to head off a PDUFA V showdown over
REMS with a flurry of public meetings and guidances, while promising all manner
of REMS upgrades in preliminary FDA-industry negotiations. At the same time,
BIO and PhRMA are both calling for a "clean PDUFA bill" free of Congressional
tinkering or manhandling, while lining up lobbyists to help them make their case
to influential members of Congress on key committees.23

CONCLUSION

Even as PDUFA V draws ever nearer, the impacts from the REMS program
initiated under PDUFA IV are unclear, except that clearly something needs to be
done. While some positive aspects were noted, these tended to be viewed as op-
portunities for improvement rather than actual beneficial accomplishments of the
REMS program as currently implemented. When stakeholders from every perspec-
tive in the system agree that the program is overly burdensome, not very effective,
and actually leaves them worse off than before, the clarion call has been sounded
widely and needs to be heeded wisely.

22 Derrick Gingery, Antibiotics Need REMSfor Public, Not Patient, Safety Reasons, IDSA Says,
THE PINK SHEET (September 13, 2010), (Vol. 72 ,No. 37, Page 15).
23 Usdin2011supra note 18.