NEWS
Oncologists Want FDA To Rethink REMS
By Merrill Goozner
coalition of cancer care stakeholders to providers. More stringent REMS can
organized
by
the
National also include what is called elements to assure
Comprehensive Cancer Network safe use (ETASU) such as having patients
(NCCN) is pressing the U.S. Food and Drug sign consent forms, requiring that physicians
Administration to make major changes in how receive specialized training, or restricting
it deploys risk evaluation and mitigation strat- where the drug may be sold or used.
Ten of the first 19 drugs given REMS by the
egies (REMS) for widely used cancer drugs.
The two REMS drawing the biggest con- FDA are frequently prescribed by oncologists
cern are for anemia-treating, erythropoietin- and hematologists, according to a recent white
stimulating agents (ESAs), whose paper published in September in the coalition’s
requirements become fully operational next journal, JNCCN. The paper emerged from an
February, and pain-treating opioids, now NCCN task force formed last year. Most of
under review at the agency. A first draft of these cancer-related REMS are for supportive
the opioid REMS is expected early next year. care such as controlling pain or avoiding anemia.
The idea behind the REMS program is to
make sure that patients are fully informed Increased Burden
about the risks of certain drugs. ESAs, once The ESA REMS was promulgated last
taken by about half of cancer patients to treat February and included most of the safe-use
chemotherapy-associated anemia, have been elements. Even before its adoption, NCCN
associated with increased risk of cardiovascu- pulled together a coalition of stakeholders
lar disease and death in trials with several to press their concerns with FDA officials,
types of cancer. When prescribing them, phy- including a series of private meetings in
sicians must follow certain procedures under March and April.
REMS, steps that some oncologists say are
“We recognized that REMS are inevitable
reducing the quality of patient care. Although and were not going to go away,” said Philip
the FDA has not modified the rules in Johnson, the pharmacy advocacy director for the
response to comments from oncologists, it Moffitt Cancer Center at the University of
says it is working to streamline and stan- South Florida and lead author of the NCCN
dardize the process.
white paper. “Our goal was to ensure that each
The agency’s REMS authority stems from one has input from the providers, that there’s
events surrounding the market withdrawal of some consistency so we can build in some effithe pain reliever rofecoxib (Vioxx) in late 2004. ciency to the process, and finally that they’re
The 2007 FDA Amendments Act authorized accomplishing what they’re intended to do.”
the agency to order a manufacturer to follow a
A voluntary survey of NCCN’s memberREMS if regulators determine that special ship, which elicited 601 domestic responses from
steps are needed to
the 96,000 physicians,
ensure that dangerous
nurses, physician assis“If you have 10 minutes to
side effects posing a
tants, and pharmacists
substantial potential
in its database, found
talk to a patient, and you
for harm don’t outthat most either agreed
weigh the benefits of a spend 5 minutes talking about or strongly agreed that
drug’s continued use.
REMS, will they get shorted REMS requirements
Those special steps
will interfere with
can include drawing on talking about the disease?” patient care (55%) and
up a special medicawill drive utilization
tion guide or a package insert that highlights toward drugs without REMS (60%). The time
the risks for patients and adopting special burden was also a considerable factor for responprograms to communicate that information dents, according to Johnson. Two-thirds of the
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respondents spent up to 4 hours per week
dealing with REMS requirements, whereas 23%
did not deal with REMS drugs at all.
“If you have 10 minutes to talk to a patient,
and you spend 5 minutes talking about REMS,
will they get shorted on talking about the
disease?” Johnson said. “That is the fear—that
we’ll spend less quality time with our patients.
Drug toxicity is important, but not to the
degree that we have to go into that much detail.”
The task force consisted of representatives
from eight cancer centers, three pharmaceutical companies (including Amgen, which
makes ESAs), a pharmacy benefit management
firm, a drug distributor, an oncology group
practice, and a patient advocacy group. NCCN
also put Scott Gottlieb, M.D., on the task
force, a political appointee at the FDA during
the George W. Bush administration and now
a scholar at the American Enterprise Institute,
a conservative Washington think tank.
The task force criticized the FDA for
failing to incorporate provider feedback into
the final REMS. It recommended that the
FDA develop a system of standardized risk
categories with a corresponding set of standard REMS requirements for each category to
minimize the regulatory burden on oncology
practices. It also wants the FDA to rewrite
medication guides to include information
about the benefits as well as risks of the drugs,
include provider and patient advocacy groups
in the discussions leading up to a REMS, and
develop methods of assessing the effectiveness
of REMS on improving patient outcomes
once they are in use.
FDA Plans
The FDA confirmed its
talk with the NCCN coalition as well as other
stakeholder groups and
is working to address
Philip Johnson many of the task
force’s concerns. “FDA is currently developing a plan for how sponsors should leverage existing data standards to make
their ETASU REMS compatible with existing
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NEWS
pharmacy management systems,” a spokesperson said. “In addition, FDA is in the planning
stages for a series of projects that focus on methods
to assess the impact of REMS . . . and developing criteria for requiring REMS with ETASU.”
The alleged lack of balance in the ESA
REMS was a primary motivation for the task
force, Johnson said. “You have to talk to the
patient once a month, and the boldest statement
in it says that the patient must acknowledge that
taking ESAs could contribute to death. Yes, it
can contribute to your death if you’re taking
more than what is recommended by the FDA.
jnci.oxfordjournals.org
But if you take the drug appropriately, there
isn’t any evidence to show that it contributes to
accelerating your death,” he said. “The information in the current REMS is not objective.”
ESA usage has dropped sharply in recent
years, beginning in 2007 with publication of
the data on their risks and a change in Medicare
reimbursement policy a year later. The
REMS wasn’t published until February 2010.
In a prepared statement, FDA spokesperson
Crystal Rice said that the agency “recognizes the
unintended increased burden on the health care
system imposed by requiring multiple unique
REMS programs, and we are committed to
developing more standardized risk management
tools and encouraging programs that use existing or developing electronic systems to implement the REMS. We have also taken steps to
get manufacturers to work together to develop
common procedures for certification, training,
and enrollment for REMS programs.”
The looming classwide REMS for opioid
drugs also weighed heavily on the task force’s
deliberations. Since announcing plans to institute
an opioid REMS in February 2009, the FDA has
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Oncologists Want continued from page 1749
received more than 2,000 public comments and
held two well-attended public meetings. Both
NCCN and the American Society of Clinical
Oncology fear that a restrictive risk mitigation program may exacerbate the long-standing
problem with pain medications: They say that
many oncologists undermedicate their patients
for pain and many patients reject taking the
drugs because they fear becoming addicted.
No Risk of Addiction
“One of the motivating factors for the REMS is
overprescription of narcotics in the general population for people with pain, and that’s a legitimate
concern,” said Richard Schilsky, M.D., a professor of medicine at the University of Chicago
and deputy director of its comprehensive cancer center. “But in the cancer population, there’s
no risk of addiction and oncologists are generally well versed in how to do narcotic pain management. To take a one-size-fits-all approach to
the opioids and lump in the cancer patients with
people with low back pain doesn’t make sense.”
“A medication guide is not much of a
concern depending on how the information is
conveyed,” added Emily Mackler, Pharm.D.,
a clinical pharmacist at the University of
Michigan’s Comprehensive Cancer Center
who served on the task force. “If there’s a
big emphasis on abuse and addiction, it could
result in bigger problems for us in terms of
getting patients to take their medication.”
A classwide REMS for opioids could also
become an administrative nightmare if firms
that make the drugs develop their own compliance programs. For example, the FDA
“We use ESAs on many patients.
We go over the stuff with them.
It’s not incredibly complicated.”
ordered makers of fentanyl buccal soluble film,
a quick-acting opioid patch placed inside the
cheek, to develop REMS because of the drug’s
growing popularity among addicts. Companies
that made the drugs made the rounds of cancer centers to discuss their pending programs.
“We told them having every company develop their own process and their own database (for keeping track of physicians who’ve
been trained in proper use of the drug) would be
jnci.oxfordjournals.org
an incredible amount of work,” said Steven
Fijalka, Pharm.D., who manages oncology pharmacy at the University of Washington Medical
Center. The center had already implemented a
REMS-like physician training and patient education program for lenalidomide and thalidomide, whose strict controls preceded the new
law, and installed special software to keep track
of patient permissions and physician training.
“Having a centralized and standardized way
of dealing with all companies would be more
than helpful,” he said. “It needs to be done on
the national level rather than us dealing with 20
different companies with 20 different drugs
with 20 different training programs.”
Not all cancer centers or oncologists share
the task force’s concerns. “Physicians will come
on board with these guidelines and mandates
from the FDA because most physicians have the
best interest of their patients in mind,” said John
DiPersio, M.D., Ph.D., chief of the division of
oncology and deputy director of the Siteman
Cancer Center at Washington University
School of Medicine in St. Louis. “We use ESAs
on many patients. We go over the stuff with
them. It’s not incredibly complicated.”
A transplant physician, DiPersio said that his
experience with ESAs—which reduce the need
for transfusions that potentially expose patients to
antibodies that can cause organ rejection—followed a familiar path. “Two things happen in
medicine. You initially use a drug when it’s available. Then there’s a period of time when you use
it unconsciously, more often, often without
meaning. When you see these toxicities and have
to follow a REMS program, it does make you
think twice about when to
use these drugs,” he said.
And, he said, it has not
scared patients away from
taking the drugs when
they are needed. He said
none of the 70 oncologists John DiPersio, M.D., Ph.D.
who practice at his center have had a single patient
read the medication guide and refuse treatment.
“That’s the power of the physician relationship
with the patient,” he said. “It’s enormous. If a
physician says it’s necessary to raise their hemoglobin, they’ll do it.”
© Oxford University Press 2010. DOI: 10.1093/jnci/djq491
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