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REMS: The New Reality
Kuyler Doyle, Principal Consultant, Campbell Alliance
Jay Jauregui, Senior Practice Executive, Trade and Distribution Practice
Gary Tyson, Senior Vice President, Clinical Development and Medical Affairs Practices
Introduction
The Food and Drug Administration Amendments
Act (FDAAA) of 2007 ushered in an increase in
regulatory authority for drug safety enhancement,
including the power to require post-approval studies
or clinical trials, label changes, or implementation of
a Risk Evaluation and Mitigation Strategy (REMS).
Since implementation, the number of products
requiring REMS programs has continued to rise.
Pharmaceutical and biotechnology companies
are realizing that the new restrictions from REMS
programs are a permanent part of the industry
landscape and that they must adapt accordingly.
This article highlights the challenges of the new
regulatory restrictions, lists potential competitive
advantages to these programs, and describes how
organizations need to adjust to the evolving risk
mitigation landscape.
History of Risk Minimization
Programs
Withdrawals of several high profile drugs from the
market elevated concerns about pharmaceutical
product safety and increased public scrutiny of
FDA practices. In response, Title IX of the FDAAA
amended the Federal Food, Drug, and Cosmetic Act
(FDCA) to authorize the FDA Secretary to require a
REMS program on any product, pre- or post-marketing, if deemed necessary to ensure that the benefits
of the drug outweigh its risks.
Although this increased regulatory authority appears to be a paradigm shift, drug risk management
has evolved over the course of several decades. The
original FDCA of 1938 allowed drugs to be marketed
once proven to be safe. However, birth defects
associated with thalidomide in Europe and Canada
during the late 1950s and early 1960s led to the
passage of the Kefauver-Harris Amendments in
1962, requiring companies to demonstrate efficacy
in addition to safety in order to be marketed. Since
then, the FDA process of approval has been founded
on a favorable benefit to risk ratio.
Table 1 – Modern Risk Minimization Tools
Attribute
RiskMAP
REMS
Dates of Activity
2003 to 2007
2007 to present
Goals
Steps to achieve specific goals and
objectives to minimize product risks,
while preserving benefits
Steps to ensure that the benefits of
the drug outweigh the risks
Author
FDA
Congress
Key Documentation
Premarketing Risk Assessment, Good
Pharmacovigilance Practices and
Pharmacoepidemiologic Assessment,
and Development and Use of Risk
Minimization Action Plans,
2005 (finalized)
Food and Drug Administration
Amendments Act (FDAAA), 2007
Impact on
Manufacturers
Suggested
Mandatory
Non-Compliance
Penalties
None
Fines and Possible Injunction
Throughout the evolution of risk management,
special programs were instituted on a case by case
basis for specific drugs as deemed necessary.
Early examples emphasized the communication
of risks to stakeholders. Initially, prescribers were
the primary target of this information in the form of
product labels, “Dear Healthcare Provider” letters,
or black box warnings. Subsequently, drug makers
were required to educate patients regarding product
risks, initially in the 1970s through patient package
inserts (PPI) that were first implemented with oral
contraceptives, and in the late 1990s with mandatory medication guides for select drugs that were
distributed to patients at the time of dispensing and
included information required for safe and effective
use. The FDA implemented its first program that
restricted drug access in 1990 with the “no blood,
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no drug” campaign for clozapine that required a
patient blood count to test for agranulocytosis prior
to dispensing.
In 1998, the FDA approved the use of the teratogenic
drug thalidomide, the very product that led to the
increased burden of proof for market approval, to
relieve complications from leprosy. Drug manufacturer Celgene developed a strict program called the
System for Thalidomide Education and Prescribing
Safety (S.T.E.P.S.®) in which only registered physicians could prescribe the drug, and then for only
one month intervals. Further, pharmacist registration was required to dispense the product, women
of childbearing age had to undergo mandatory
pregnancy tests, and both men and women had
to adhere to birth control methods. Subsequently,
REMS: The New Reality
Table 2 – Consideration Factors for REMS Requirement
Market Stage
Factors
Size of the population likely to use the drug
Seriousness of the disease
Expected benefit of the drug with respect to disease
Expected duration of treatment
Seriousness of known or potential adverse events related to the drug
Whether drug is a new molecular entity
Pre-approval
ew safety information deems a strategy is necessary to ensure the
N
benefits outweigh the risks
“New safety information” may be derived from a clinical trial, an adverse event report, a post approval study, or peer reviewed literature
Post-approval
Table 3 – Elements of REMS
Element
Access
Education
Assessments
Description
Timetable for
Submission of Assessments of the REMS
equired of all REMS
R
Assess by 18 months, by 3 years, and in 7th year after REMS approval
FDA may increase frequency of assessments or eliminate requirements
after 3 years
Assessment within 15 days for cause
Medication Guide or PPI
edication guides are distributed to patients when drug is dispensed
M
Patient package inserts may be required if they might help mitigate
serious risks of the drug
Communication Plan to
Healthcare
Professionals
ecessary when FDA determines a plan may support implementation of
N
an element of REMS
May be through letters to healthcare providers or through professional
societies about drug risks and safety protocols
Elements to Assure
Safe Use (ETASU)
E TASU need to be commensurate with risk
Must be posted publicly within 30 days of being imposed with an
explanation of how elements will mitigate risk
Will not be unduly burdensome on patient access (due to life threatening diseases or difficulty accessing healthcare)
To the extent practicable, should minimize the burden on the health
care system and should be compatible with current distribution system
ETASU options:
Prescribers must have training or certification
Pharmacies, practitioners, or healthcare settings that dispense the
drug must be certified
Drug must be dispensed only in certain healthcare settings
Drug is dispensed to patients only with documentation of safe-use
conditions, such as laboratory test results
Patients must be subjected to monitoring
Patients must enroll in a registry
Implementation System
ay by required to monitor and evaluate implementation of ETASU eleM
ments by those responsible, and to work to improve implementation
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thalidomide has been found to be effective for other
indications as well, including multiple myeloma,
and the S.T.E.P.S. program continues to be in use.
Programs such as S.T.E.P.S. helped pave the way for
the modern era of risk minimization.
Following the Prescription Drug User Fee Act (PDUFA)
and attempts at shortened review cycles, there were
concerns about the marketing of products prior to
being fully vetted as safe. In response, the FDA established a new risk management system with PDUFA
III in 2002, and published final guidance for its Risk
Minimization Action Plan (RiskMAP) in 2005. The goal
of the RiskMAP was to elevate the appropriate use of
products and to decrease adverse events. Sixteen
accepted RiskMAPs were carried over and deemed
approved REMS when the FDAAA went into effect in
March of 2008. In fact, many of the post-marketing
elements that define REMS programs also made up
RiskMAPs, including the education of patients and
physicians and restricted access, although there are
also distinct differences (Table 1). While RiskMAPs
were voluntary, the FDA now has the ability to mandate these restrictions based on the powers provided
in the FDAAA amendment, and can impose fines of
up to $250,000 per violation on manufacturers for
non-compliance.
Components of REMS Programs
A REMS can be required of any manufacturer in all
stages of development, including pre-licensure,
review, and post-market. To determine if a REMS is
needed, the FDA examines risks for serious side effects, potential for misuse of the drug, and whether
off-label usage needs to be minimized. During
the drug review process, the FDA will consider the
amount of information known on the product or
drug class in relation to the size of the target population, treatment length, number of reported adverse
events, and severity of the indication to be treated
(Table 2). REMS may be requested of products that
are already on the market due to reports of adverse
events via post-marketing surveillance, or due to
safety concerns arising from new data from phase 4
studies or literature reviews.
All REMS must include a timetable for submission
of program assessments, which are required to
be completed by 18 months, 3 years, and in the
7th year. The other REMS elements vary at a level
commensurate to the risk anticipated by the FDA,
and may consist of education-based mandates
or elements to ensure safe use (ETASU)(Table 3).
Figure 1 – Four Tiers of REMS Complexity
Less Severe
More Severe
Minimal
Low
T imetable for submission of
assessments
Medication guides or patient
package inserts
Specific package insert
language
Periodic adverse events reports
and continuous monitoring
C ommunication plan to disseminate safety information to
healthcare providers
Educational material packages
Patient acknowledgement
forms (e.g., understanding of
risk)
Follow-up surveys to assess
the educational program
Educational elements can contain requirements
for medication guide outreach, PPI, or the need
for a communication plan to healthcare providers. ETASU include access restrictions via patient
testing or screening for eligibility, patient registry
and tracking, prescriber training or certification, and
drug distribution limited to certified pharmacies or
healthcare settings. REMS programs may further
require approval of an implementation system to
monitor and evaluate ETASU execution.
Based upon the severity of the requirements, REMS
generally fall into one of four tiers in severity (Figure
1). As perceived risk with the drug increases, the
complexity of the REMS elevates accordingly. While
most REMS programs required thus far have fallen
into the “minimal” category and nearly 75% have
required only medication guides (Figure 2), complex
REMS have also been employed. The drug Entereg®
(Adolor and GSK) facilitates healing following bowel
resection, but is required to have the most severe
form of REMS where access is controlled due to evidence of increased ischemic cardiovascular events.
The manufacturers established the Entereg Access
Support and Education (E.A.S.E.™) program, which
restricts drug dispensing to only registered hospitals
and tracks the patient to limit the duration of therapy.
Advanced
Complex
Certification and training of
prescribers
Certification and training of
pharmacists and site-of-service
staff
Recertification and product release approval at each dispense
Limited distribution to only
registered sites of service (e.g.,
hospitals)
Regular audits of prescribers
and dispense locations
Not only does the FDA have the power to require
REMS for individual products, it can also mandate
REMS for entire drug classes. This power has been
exercised for fluoroquinolone antimicrobials, requiring label changes and medication guides. In February
2009, the FDA notified manufacturers of opioid drugs
that a class-wide REMS was in development. Due to
the tens of millions of prescriptions written for opioid
drugs each year, implementing a REMS for this drug
class will be a massive undertaking. Other classes of
drugs discussed as possibly requiring REMS are the
erythropoietins, tumor necrosis factor blockers, antidepressants, botulinum toxins, and anti-epileptics.
Challenges of REMS
Although an increased focus on drug safety is a
positive advancement, the new regulatory authority
provided to the FDA certainly poses challenges
to drug manufacturers and can obviously impact
the bottom line (Table 3). As the requirements for
REMS programs are still relatively new, they add an
additional layer of preparation and uncertainty into
the regulatory process for new drugs. Also, REMS
negotiations can assign additional time to the approval process and lead to costly launch delays.
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P atient screening
Patient enrollment into
registries
Patient record audits (e.g., duration of therapy limits)
Implementation systems
In addition to revenue impact from a delayed
launch, there are also clear and significant costs associated with these programs. In its simplest form,
medication guides to satisfy REMS requirements
add substantial costs for production and dissemination. Effective training programs may need to be
developed and employed for healthcare providers.
Maintaining patient and physician registries is not
a trivial feat, and will require expenditures for software to manage and track confidential data. Registries will also necessitate budgeting for full time
employees or contractors to design, implement, and
administer. Further, scheduled REMS assessments
require sponsors to reveal that their program is
effective. The assessments need to demonstrate
whether the ETASU are meeting their goals, so these
data will have to be tracked and analyzed.
The more rigorous the REMS program becomes,
access is increasingly restricted to patients, likely
shrinking volume in sales. Even the lightest REMS
requirements, medication guides, can be a burden
on prescribers when they include a patient-physician agreement to sign. The additional paperwork
associated with REMS can dissuade physicians from
prescribing the product. Further, REMS that include
limits to distribution or duration of therapy can lead
REMS: The New Reality
Figure 2 – Profile of Accepted REMS Programs
to a reduction in revenue, making the product less
commercially attractive to the manufacturer.
Potential Advantages
100%
80%
60%
40%
20%
0%
MG Only
MG + CP
MG + ETASU
+ IS
MG + CP +
ETASU + IS
CP + ETASU
+ IS
MG = Medication Guide ETASU = Elements to Assure Safe Use
CP = Communication Plan IS = Implementation System
Note: n=89. Data obtained from FDA website November, 2009
When properly planned and executed, REMS
programs can also offer some potential advantages
(Table 4). First, through its mandated programs to
improve drug safety, REMS has provided the ability
for the FDA to approve products that likely would have
never made it to market. Patients with indications
that have high unmet needs desperately want new
medications, and are frequently willing to accept
some risk for the potential benefits. In requiring
both the patients and physicians to be well versed
with the risks associated with the products, the FDA
is allowing these medications to move forward by
making sure the practitioner and patient fully comprehend correct use of the product as well as possible
outcomes. At the same time, a clearer understanding
of proper usage of the drug can lead to increased
adherence, helping to maintain sales while potentially
reducing the risks associated with improper use.
REMS programs allow organizations to establish
relationships via registries with two key stakeholders, patients and physicians. Up-to-date patient
registries allow active monitoring of drug usage,
Table 3 – REMS Challenges
Challenge
Description
How to Prepare
Regulatory Uncertainty
EMS requirements are relatively new, and add an
R
additional layer to the approval process
Can lead to delay of launch , thereby reducing
revenue
P roactively plan for REMS and communicate with
regulatory officials during development
Plan REMS programs early enough to avoid approval
delays
Costs Associated with REMS
Programs
EMS programs will increase costs
R
Tracking patient information will require management software and full time employees
I ntegrate REMS planning into the organization and
design SOP around the activities that emphasize
efficiencies
Design REMS programs that specifically match
program activities with drug risk to minimize scale of
the program
Paperwork Can Dissuade
Healthcare Providers from
Prescribing
I ncreased REMS complexity expands the requirements for healthcare providers to track patients,
amplifying workload
More work for prescribers can dissuade drug use,
thereby reducing sales
E stablish a knowledgeable and dedicated group
that can design effective REMS programs with the
stakeholders in mind to minimize burden
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Table 4 – Potential REMS Advantages
Advantage
Description
How to Benefit
Ability to Market Drugs with
Some Safety Risk
EMS provides ability for FDA to approve products
R
that likely would not have made it to market
Requires patients and physicians to be fully aware of
the drug and its risks
P rovides a means to fulfill unmet needs in the market
Clearer understanding of safe use of the drug could
lower risk and maximize benefit, thereby increasing
adherence
Ability to Establish Relationships
with Stakeholders
EMS requirements for registration or training of
R
patients and physicians provides an opportunity to
establish a relationship with key stakeholders
eep stakeholder needs in mind when developing
K
REMS programs
When done effectively, can provide positive impact
on the brand and the drug manufacturer
Complex REMS Could Lengthen
Life Cycle
eneric entrants are required to establish a single
G
shared REMS system for ETASU unless burdensome
or patented
Access restrictions could make it difficult for generic
manufacturers to obtain product for equivalency
testing
evelop a novel, distinguishing REMS program that
D
contains unique components with potential for intellectual property
adherence, and adverse events. Interestingly, patient
registries also share many aspects in common with
health management or support programs developed
for some specialty drugs. As such, REMS registries
provide an opportunity for companies to establish
a connection with patients through personalized
interactions regarding adherence and safe use or by
setting up web portals for peers who are undergoing
the same treatment and who are looking for relevant
information regarding their disease and therapy.
When carried out effectively, these programs can
build communities that foster brand loyalty. In a time
when therapeutic areas are becoming increasingly
crowded, patients and physicians have options for
their product of choice. A well designed REMS registry
and information network can be an effective means
of brand differentiation and could, depending on the
level of unmet need, potentially allow for premium
pricing to offset the costs of the program. Distinguishing factors within REMS programs will also come
into play when class-wide REMS are required.
Although many view REMS that limit distribution
as measures to restrict access, they could also in
effect increase the lifecycle of a drug. Restrictive
REMS hold the potential to stave off generic competition, as they may find the space less attractive
due to the complex and costly programs. The FDAAA
states that upon generic entry, the new competitor
must use a single, shared system of ETASU with the
originator product. This requires generic manufacturers to work with the innovator companies to
establish the single system, or request a waiver
for this requirement if the burden of creating it outweighs the benefits. Another potential to waive the
single system requirement comes if the innovator
company has active patents related to their novel
risk mitigation plans, and the generic manufacturer
is unsuccessful in obtaining a license to use aspects of the ETASU. Some companies have already
filed patents for elements of their risk mitigation
programs, such as patient screening algorithms,
and a novel REMS program could remain a barrier to
entry, point of market differentiation, or source of
revenue through license agreements. Further, the
limited product distribution imposed by REMS can
make it difficult for generic competitors to acquire
the drug in order to perform the comparative evaluations required for the abbreviated approval process,
as already seen with Celgene’s Revlimid®, thereby
delaying entry into the market.
How to Adapt
Although Title IX of the FDAAA provides authority to
ensure post-market drug safety, there is likely to
be increasingly less uncertainty surrounding the
need for REMS requirements for new drugs, and
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companies will be required to take a close look at
safety issues earlier in the development process.
To adjust to the emerging risk mitigation environment, pharmaceutical companies need to alter their
outlook, preparation, and execution of REMS.
Outlook
To minimize the possibility of regulatory delays due
to REMS negotiations, organizations need to adopt a
proactive outlook toward risk mitigation rather than
a reactive one. Manufacturers should pursue pre-submission interactions with regulatory officials during
the development process to limit late surprises that
could impede launch. Pre-submission interactions
with the FDA will allow discussions of drug safety profiles that could inform product managers regarding
needs for appropriate REMS requirements.
Organizations must assess the impact of REMS
activities on all stakeholders when developing
potential REMS programs. As REMS requirements
could potentially be used for competitive advantages, the pursuit of novel programs that benefit
patients and physicians while minimizing the paperwork burden could be beneficial. The formation of a
knowledgeable and dedicated group to design effective and innovative REMS could afford organizations
the ability to develop programs that set the bar for
a drug class.
REMS: The New Reality
Preparation
Since the development and negotiation of REMS programs can require a considerable amount of time,
companies need to initiate preparation for a REMS
proposal early in new product planning. If clinical
trials suggest that there may be some safety issues
that the FDA will scrutinize, the manufacturer should
assume they will need a REMS program.
Analysis of FDA actions related to the prior negotiation and approval of REMS programs will help to plan
proposals for pipeline products. REMS should be
designed to match associated risks of the drug with
specific activities, thereby keeping the scope of the
program in check to control costs. Marketing will
need to determine how a proposed REMS program
would likely affect the revenue forecast and commercial viability of a product. Planning ahead will
help alleviate the challenges associated with late
stage design and negotiation of a complex REMS.
Execution
As REMS programs appear to be a part of the permanent regulatory process, organizations must also
improve the ability to assess, plan, and implement
programs by integrating them into the company
DNA and making them part of a new routine. Clearly
the clinical, regulatory, safety, distribution, marketing, sales, and medical affairs functions need to
be involved in REMS scenario planning for new
products. Although committees that develop REMS
programs will be cross-functional in nature, a
permanent “home” for the management of activities
must be established within the organization and a
standard operating procedure (SOP) developed.
Inclusive discussions with internal stakeholders to
define the SOP will define roles and responsibilities
for REMS development and facilitate buy-in to the
protocol, a requirement to make REMS execution
an efficient process. Companies must also define
REMS activities that will be performed in-house
versus outsourced, and vender partners must be established. A means to monitor REMS effectiveness
must also be generated, including the ability for
sales and medical affairs field teams to report back
on prescriber sentiments towards requirements. Efficiencies in REMS design and execution will further
help provide credibility to the FDA that can facilitate
future program negotiations and minimize costly
delays.
Conclusion
REMS is clearly part of the new landscape of the
pharmaceutical industry. Companies must accept
this reality and adjust their organizations accordingly. Comprehension of the potential REMS triggers,
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the program approval process, and early planning
will help alleviate some of the challenges posed by
a complex REMS and will help avoid costly delays to
drug approval. Companies need to integrate REMS
development as a permanent part of the organization and work to create a SOP that will allow for best
practice development in the assessment, planning,
and implementation of programs. A full appreciation
of the impact of REMS requirements on key stakeholders is critical to the generation of programs to
reduce risk while remaining commercially viable.
Through establishment of skill sets needed to
understand and generate effective REMS programs,
companies will be able to capitalize on potential
competitive advantages of a well-designed REMS,
despite the associated challenges.
Note
This white paper is being offered as a background
article in preparation for the public release in early
2010 of Campbell Alliance’s survey results regarding
the “State of REMS Today.” The survey will provide a
snapshot of how companies across the industry are
currently planning and executing REMS programs.
To set up a time for us to share the results of this
research, please contact Gary Tyson.
Gary Tyson
[email protected]