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w w w. h e a lt h a f fa i r s .o r g
Health Policy Brief
u p dat e d a p r il 9 , 2 0 1 5
Right-to-Try Laws. Some states have passed
legislation intended to expand access to
experimental treatments for patients with
serious or life-threatening conditions.
what’s the issue?
Under current federal regulations, patients
with serious or life-threatening illness have
two primary options to access experimental
therapies that may treat their condition but
that have not yet been approved by the Food
and Drug Administration (FDA). The most
straightforward path is to participate as a human subject in a clinical research trial. For
patients who cannot be enrolled in that trial
(because of their medical status or geographic location, for example), a second option is
to apply to the FDA for access to the experimental drug under the expanded access (also
known as compassionate use) program, which
was created to allow seriously ill patients to
access treatments they would not otherwise be
eligible to receive.
©2015 Project HOPE–
The People-to-People
Health Foundation Inc.
10.1377/hpb2015.4
In the past four years the FDA has received
nearly 6,000 expanded access applications
and denied just thirty-three. However, critics
of the program argue that the process is too
cumbersome and that it discourages many patients and physicians from applying. Since last
year, more than twenty states have introduced
laws aimed at making experimental therapies
more easily accessible to patients with terminal illnesses, thirteen of which have been
signed into law. These laws are often called
Right-to-Try laws. Supporters argue that patients have the right to determine what risks
they are willing to undertake to save their own
lives and that these laws help reduce unnecessary federal interference. Opponents argue
that such laws may introduce new risks for patients while undermining laws meant to protect public safety. The ultimate effects of these
state-level efforts are still unclear, and their
constitutionality is open to question.
what’s the background?
Clinical testing of an experimental drug is
typically a three-phase process. Phase I trials
are small (20 to 80 patients) and are used primarily to evaluate safety and dosing ranges,
usually in healthy volunteers. Phase II trials
are larger (typically 100 to 300 patients) and
are designed to show early evidence of efficacy in the patients that the drug is intended to
treat. Phase III trials may include hundreds or
thousands of patients and are used to demonstrate that the drug is effective compared to
a control (such as a placebo or a comparator
drug). Typically, a manufacturer may submit
an application to the FDA for marketing approval once a drug has successfully completed
Phase III trials.
h e a lt h p o l ic y b r i e f
“Supporters argue
that patients
have the right
to determine
what risks they
are willing to
undertake to
save their own
lives.”
r ig h t-t o -t r y l aw s
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The clinical research process is tightly regulated in the United States. Any drug company
wishing to conduct a clinical trial must first
submit an Investigational New Drug (IND) application to the FDA, which allows the company to manufacture the drug and ship it across
state lines for use in the trial. The drug may
be only administered to patients who are formally enrolled in that clinical trial. For some
patients, however, participation in a clinical
trial is not possible. The study population for
that trial may be limited based on any number
of factors, including specific diagnosis, age,
stage of illness, or comorbidities. Patients may
also be too sick (or lack the financial means)
to travel to a clinical research site where the
trial is taking place.
submission requirements governing the application process for a single person. This lack of
formal criteria prompted charges that the FDA
was being inconsistent in its approach, which,
in turn, was leading to inequitable or preferential access for certain groups of patients.
In 1997 Congress passed the FDA Modernization Act, which created the statutory basis for
single patients and intermediate-size patient
populations to be granted expanded access.
federal regulation of expanded access:
For these patients, a second option is to apply
to the FDA for access to unapproved therapies
under the expanded access program. This
program allows patients who meet certain eligibility requirements to receive an experimental therapy for treatment purposes rather than
as part of the formal clinical research process.
Intermediate expanded access may be applied to any group of patients that is greater
than one but that does not reach the threshold for expanded access under a treatment
IND or protocol. Intermediate expanded access programs are sometimes used to aggregate multiple single-patient expanded access
applications for the same drug. They may also
be used for drugs that are not currently being
developed for marketing approval or that are
no longer on the market.
An application for expanded access can be
submitted by either the manufacturer or a
licensed physician. The FDA currently maintains three general categories of expanded
access: treatment, single patient, and intermediate. Each of these categories, described
below, is further split into two subcategories.
One is “expanded access INDs”—through
which the manufacturer submits a separate
IND for a patient or group of patients—and the
other is “expanded access protocols,” whereby
the manufacturer amends the protocol under
an existing IND to include the patient (or patients) seeking access.
Treatment INDs and protocols are the oldest
form of expanded access, having been formally established in federal regulations in 1987.
Under this category, a relatively large group of
patients (hundreds or thousands) are permitted to access an experimental drug, provided
that the sponsor is actively pursuing FDA approval and is in later stages of testing (or has
already submitted trial results to the FDA for
review). The formalization of this process
was largely in response to activism by AIDS
patients, who lobbied strongly in support of
early access to the drugs being developed to
treat their disease.
While individual patients were able to access
experimental therapies under treatment INDs
or protocols, there were no formal criteria or
Single-patient expanded access is, as its
name implies, used for individual patients. It
may be granted on either a standard basis or,
for patients who do not have time to acquire
written authorization from the FDA, on an
emergency basis.
For all three categories, patients may be
granted expanded access if under the following conditions: The patient has a serious or
immediately life-threatening condition; the
patient’s physician has determined that no
alternative comparable or satisfactory treatment is available, is willing to administer the
experimental therapy, and obtains Institutional Review Board (IRB) approval for the
patient to use it; the FDA determines the risks
associated with the treatment do not outweigh
the potential benefits to that patient; and providing the experimental therapy to the patient
will not interfere with the broader clinical investigation that will ultimately support a marketing application.
Depending on the category, additional considerations may apply. For single-patient applications, the risks of taking the drug (to the
extent this is known) must not outweigh the
risks associated with the patient’s condition,
and the treatment must be limited to a single
course of therapy for a specific duration, unless the FDA authorizes otherwise. The manufacturer or treating physician is also required
to submit a written summary of the results of
the expanded access use, including any adverse events. For intermediate applications,
there must be some evidence that the drug is
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safe at the dose and duration proposed, and
there must at least be preliminary clinical evidence of effectiveness. A January 2015 article
by Jonathan J. Darrow and colleagues in the
New England Journal of Medicine provides a
detailed discussion of these three categories
as well as ongoing limits to expanded access.
6,000
In the past four years the FDA has
received nearly 6,000 expanded
access applications.
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r ig h t-t o -t r y l aw s
Once an application is submitted, the FDA
has thirty days to respond. Very few are denied. Of the 5,849 single-patient expanded
access applications (both emergency and
nonemergency) made to the FDA between
2010 and 2014, just thirty-three were rejected.
However, the FDA cannot compel a manufacturer to provide an investigational product to
a patient; it can only permit the company to do
so. Manufacturers may also impose additional
restrictions or requirements on patients who
are applying for expanded access, and—if the
FDA permits it—may charge patients (or their
insurer, if it covers experimental therapies)
for use of the drug.
The FDA revised its regulations on expanded access in 2009 and released draft guidance
to industry on the process for implementing
expanded access and on obtaining approval
to charge for it in May 2013. In February 2015
the agency released additional draft guidance
including a new streamlined application form,
which if implemented would greatly reduce
the administrative burden of applying. However, companies may still vary significantly
in terms of whether and under what circumstances they will provide the drug. Manufacturers are also not required to track or report
on the number of expanded access requests
they approve or deny, which makes it difficult
to assess how many patients are actually granted access. However, a January 2015 search of
ClinicalTrials.gov found 138 ongoing studies
that were available for expanded access.
criticism of the expanded access program: Critics of the expanded access program
have argued that the application process is unnecessarily burdensome and lengthy, which
discourages doctors and manufacturers from
applying. By the FDA’s own estimate, the current IND application can require about 100
hours to complete, and an IRB review adds an
additional layer of paperwork and potential
delay. For some, these requirements represent
an unacceptable barrier for desperate patients
seeking to access potentially life-saving drugs.
These criticisms of the FDA are not new. Instead, they reflect a decades-long debate about
the need to balance access to new therapies
against requirements that a therapy be proven
safe and effective before it can be marketed.
These federal requirements were themselves
put in place in response to highly publicized
incidents of harm caused by unsafe drugs.
Expanded access—which has evolved over
the past thirty years in response to sustained
activism by patients and other groups—represents an attempt to introduce some degree of
flexibility into the regulatory process and allow patients with no other treatment options
a chance to try therapies they may not otherwise be able to access.
In the past decade, there have been several
attempts made at the federal and judicial levels
to further relax restrictions on the administration of experimental therapies to terminally ill patients. One of the most high profile of
these efforts was led by the Abigail Alliance
for Better Access to Developmental Drugs,
which in 2003 submitted a Citizen Petition to
the FDA requesting that it make experimental
therapies available to terminally ill patients,
provided that the drug had passed Phase I testing. Following several years of litigation, the
DC Court of Appeals ruled against the Abigail
Alliance, stating that terminally ill patients
have no constitutional right to access experimental therapies. The US Supreme Court subsequently declined to review the case. At the
federal level, several (ultimately unsuccessful)
bills have been introduced that aim to relax
FDA restrictions on access to experimental
therapies. The most recent of these (HR 4475,
the Compassionate Freedom of Choice Act of
2014) failed to make it out of committee.
In the past year, the debate has shifted to the
state level, owing in part to the efforts of the
Goldwater Institute, a libertarian think tank.
In February 2014 the institute released a policy paper that outlines the major critiques of
the FDA’s expanded access program and proposes model legislation for state governments
to adopt. To date, thirteen states have enacted
a version of this Right-to-Try legislation, and
at least twenty-one others have introduced
some form of a Right-to-Try bill.
what’s in the laws?
The bills that have already been enacted
share several key characteristics, largely because the Goldwater Institute’s policy brief
included a model legislative template. All thirteen laws seek to bypass the FDA application
process and establish expanded access programs for patients meeting certain eligibility
requirements.
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Under the laws, an eligible patient must
have a terminal illness; have considered all
other treatment options currently approved by
the FDA; have received a prescription or recommendation from their physician for an experimental drug, biologic, or device; and have
provided written informed consent to undertake the risks associated with the treatment.
“Efforts are
under way to
standardize and
improve the
way in which
individual
companies
manage
expanded access.”
An experimental therapy is defined as any
drug, biologic, or device that is currently under investigation in a clinical trial and has
successfully completed Phase I safety trials.
In line with current federal regulations, none
of the laws compel the manufacturers of these
products to make them available. Unlike the
FDA process, manufacturers would not need
to obtain approval before charging for the
therapy. The laws also do not compel insurers
to cover the costs of these experimental therapies (which may include the cost of treating
unexpected side effects). Medical licensing
boards are also prohibited from taking action
against a physician for recommending or prescribing the treatment.
The laws do vary in certain respects. For
example, Arizona excludes primar y care
physicians from its definition of physician,
and Missouri excludes controlled substances
from eligibility. Most of the states (with the
exceptions of Arizona, Arkansas, Louisiana,
Missouri, and Wyoming) include statutory
language defining the minimum information
that must be communicated to the patient
through the informed consent procedure, and
all but two (Louisiana and Arizona) added language aimed at protecting both manufacturers and the treating physician from liability.
Louisiana included language that protects
prescribing physicians, but not the manufacturer, from liability. Although none of the bills
require insurers to cover the costs associated
with the prescription or administration of
these drugs, Maine specifically allows insurers to deny coverage for services provided to
a given patient for up to six months from the
time that the patient stops receiving the experimental treatment. However, in line with
federal regulations, insurers may not deny
coverage for services related to preexisting
conditions or for treatments that began prior
to the use of the investigational product.
what’s the debate?
Criticism of these Right-to-Try laws centers on
two primary concerns. First, there are ethical
concerns that patients will be exposed to significant harms with no guarantees of benefit.
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Phase I trials are just the first step in assessing safety. In many cases, serious side effects
may not emerge until later stages of research.
Although these laws do require that patients
provide written informed consent to undertake the risks associated with the therapy,
critics argue that in many cases, patients and
physicians would have inadequate data to fully
assess the risks of a given therapy. Furthermore, Phase I trials often provide little to no
information on effectiveness, which makes
it difficult to assess the drug’s benefits. Vulnerable patients may also be particularly ill
equipped to weigh the benefits and risks of
participation. One survey, for example, found
that severely ill patients had reduced ability to
understand and retain information on risks
when compared to healthy patients, which
raises important (and much larger) questions
about the adequacy of the standard informed
consent process.
Some have also raised ethical concerns
related to the fairness of these Right-to-Try
laws. Because insurers are not required to reimburse for the associated costs, access may
in practice be limited to patients with the resources to cover the costs, which could include
the direct cost of the drug—as the manufacturer defines it—as well as the medical fees
associated with its administration or the treatment of any side effects that may follow.
Second, there are concerns that broader access to experimental therapies can undermine
the ongoing clinical research that might support full FDA approval. Manufacturers—particularly small companies that have limited
financial resources or that are working in
disease areas that affect small numbers of patients—may be ill equipped to handle the extra demands placed on their staff resources or
on the limited supply of their investigational
product.
Manufacturers also worry about liability
related to adverse events and the chances that
those adverse events might reduce the likelihood of FDA approval for their drug. Broadening expanded access programs might also
deter patients from enrolling in formal clinical trials, which could further undermine the
research enterprise.
Although these concerns over safety, equity,
and the integrity of the research process are
also present under the federal expanded access program, these state laws could, if fully
implemented, intensify the problems. However, these laws are unlikely to achieve their
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stated goals for several reasons. As previously
noted, shipping an investigational drug across
state lines is illegal without an approved IND
from the FDA. Companies interested in gaining full regulatory approval for their products
are unlikely to ignore federal regulation. Furthermore, although the FDA has yet to issue
a formal position, these laws are unlikely to
withstand a legal preemption challenge. Under the Supremacy Clause of the US Constitution, federal law generally takes precedence
over state law whenever the two are in conflict.
what’s next?
It is unclear whether any patients have successfully accessed an experimental therapy
under the state laws, although this may be as
a result of low levels of awareness. However,
Right-to-Try laws have proved to be politically
popular, and there are likely to be more state
laws passed in the current legislative sessions.
It is also unclear whether the FDA will involve
itself in any legal challenges to the laws that
have already passed. However, in December
2014 the agency announced plans to establish
an expanded access working group, which will
develop policies to streamline the application
process.
About Health Policy Briefs
Written by
Elizabeth Richardson
Research Associate
Engelberg Center for Health Care Reform
Brookings Institution
Editorial review by
Joan H. Krause
Associate Dean for Faculty Development
University of North Carolina
School of Law
Jordan Paradise
Associate Professor of Law
Seton Hall University School of Law
Rob Lott
Deputy Editor
Health Affairs
Tracy Gnadinger
Assistant Editor
Health Affairs
Health Policy Briefs are produced under
a partnership of Health Affairs and the
Robert Wood Johnson Foundation.
In February 2015 the FDA redesigned its
website on expanded access and released
draft guidance that introduced a new, simplified form (Form 3926) that physicians could
use to apply for individual expanded access.
This streamlined form is intended to address
concerns that the traditional IND application
is too burdensome for individual physicians
to complete. The FDA estimates that the new
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form will take just forty-five minutes to complete, instead of the 100 hours required to
complete a traditional IND application. The
form is currently available for public comment
and is expected to be finalized later this year.
At the industry level, efforts are under way
to standardize and improve the way in which
individual companies manage expanded access. Two major industry trade groups recently delivered statements on the issue and have
developed standards and principles for their
respective member companies to follow when
developing their expanded access policy for a
particular therapy.
Legislation was also introduced at the federal level late last year (HR 5805), with the
goal of improving the existing expanded access program. If passed, the law would require
companies to provide the FDA with more information on its process for dealing with expanded access requests. It would also direct
two entities—the Government Accountability
Office and a separate, multistakeholder task
force—to evaluate the current program and
provide recommendations for its improvement. Finally, the bill would require the FDA
to finalize its current guidance on expanded
access, taking these recommendations into
account. The text of this legislation has since
been incorporated into the House Energy and
Commerce Committee’s discussion draft of
the 21st Century Cures Act, which is likely to
be introduced in the next few months. It remains to be seen how these various nationallevel efforts will impact patient decisions to
pursue expanded access under state Right-toTry laws. n
resources
Christina Corieri, Everyone Deserves the Right to
Try: Empowering the Terminally Ill to Take Control
of Their Treatment (Phoenix, AZ: Goldwater Institute, Policy Report No. 266, February 2014).
Food and Drug Administration, Guidance for Industry: Expanded Access to Investigational Drugs for
Treatment Use—Qs & As (Silver Spring, MD: FDA,
May 2013).
Jonathan J. Darrow, Ameet Sarpatwari, Jerry Avorn,
and Aaron S. Kesselheim, “Practical, Legal, and
Ethical Issues in Expanded Access to Investigational
Drugs,” New England Journal of Medicine 372, no. 3
(2015): 279–86.
Food and Drug Administration, Individual Patient
Expanded Access Applications: Form FDA 3926:
Guidance for Industry (Silver Spring, MD: FDA, February 2015).
Cite as:
“Health Policy Brief: Right-to-Try Laws,”
Health Affairs, Updated April 9, 2015.
Food and Drug Administration, Expanded Access:
Information for Patients (Silver Spring, MD: FDA,
February 10, 2015).
Sign up for free policy briefs at:
www.healthaffairs.org/
healthpolicybriefs
Food and Drug Administration, Guidance for Industry: Charging for Investigational Drugs under an
IND—Qs & As (Silver Spring, MD: FDA, May 2013).
Darshak Sanghavi, Meaghan George, and Sara
Bencic, “Individual Patient Expanded Access: Developing Principles for a Structural and Regulatory
Framework,” Health Affairs Blog, July 31, 2014.