Editorial
Should patients in need be given
access to experimental drugs?
Arthur L Caplan† & Alison Bateman-House
†
NYU Langone Medical Center, Division of Medical Ethics, New York, NY, USA
1.
Introduction
2.
Healthcare providers’ duties to
patients
3.
Who are the ‘patients in need’
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 05/22/15
For personal use only.
of experimental drugs?
4.
How do patients access
experimental drugs?
5.
Brief historical overview
6.
Current reforms
7.
Societal considerations
8.
Expert opinion
Patient access to experimental drugs outside of clinical trials is called compassionate use or expanded access. Compassionate use/expanded access presents
a powerful ethical dilemma in that it involves competing claims that both
have moral weight: specifically, an individual patient’s very understandable
desire to try to extend his or her life versus the orderly and efficient functioning of a drug development and clinical trial system that benefits much larger
numbers of patients. Patient advocates, the FDA, pharmaceutical trade
groups, and state and national legislators in the US are all currently weighing
in on patient access to experimental drugs, and new guidelines and rules are
being introduced. In this editorial, we discuss the impulse to rescue individual
patients facing dire diseases and underscore the ethical questions that such
rescue efforts raise.
Keywords: compassionate use, expanded access, experimental drugs, investigational products,
right to try
Expert Opin. Pharmacother. (2015) 16(9):1275-1279
1.
Introduction
Across the US, compassionate use -- or to use the FDA’s preferred term ‘expanded
access’ -- has become a matter of heated public debate. Patient advocates, state
and national legislators, pharmaceutical trade groups, and the FDA are weighing
in on the practice of allowing patients who are not participating in clinical trials
access to medical products that have not yet been approved by the FDA for use
or sale. Answering the question “Should patients in need be given access to experimental drugs?” is complicated because it involves competing claims that both have
moral weight: an individual patient’s very understandable desire to try to extend his
or her life versus the orderly and efficient functioning of a drug development and
clinical trial system that benefits much larger numbers of patients.
2.
Healthcare providers’ duties to patients
A healthcare provider has a duty to try to help his or her patient. However, healthcare providers also have a duty not to harm patients, which generally outweighs the
duty to try to help. Thus, healthcare providers have to make balancing decisions,
trying to avoid doing harm, trying to help, and, more often than not, trying to
ensure that any harm inflicted will be outweighed by the expected benefits of the
intervention.
Such balancing decisions are even more complicated when they involve the use of
experimental drugs. In the US, it is the FDA’s mandate to ensure the safety and efficacy of drugs available on the market. By using an unapproved drug, a healthcare
provider and patient forego this protection. As such, it would generally be inappropriate to try an experimental drug when an approved one is available. Thus, even if a
healthcare provider, patient, or both are convinced that an experimental agent will
cure the patient’s illness, it may not be used if an approved drug is available. Clinical
trials constitute an acceptable exception to this rule.
10.1517/14656566.2015.1046837 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666
All rights reserved: reproduction in whole or in part not permitted
1275
A. L. Caplan & A. Bateman-House
In the case where no approved drugs are available, a healthcare provider may, under certain circumstances, ethically try
an experimental drug. First, the patient must be informed
that the treatment is experimental, the outcome unpredictable
and possibly harmful. Second, the patient’s participation must
be voluntary or, if the patient is unable to voluntarily consent,
participation must be approved by the patient’s surrogate
decision maker.
3. Who are the ‘patients in need’ of
experimental drugs?
companies often wish to isolate such data from that derived
from clinical trials. In the US, emergency use of an experimental drug requires advance approval by the manufacturer
of the experimental drug, the FDA, and the institutional
review board (IRB) of the facility where the attempt will be
conducted [2]. The manufacturer has no obligation to make
an experimental drug available and may say no without legal
repercussion. According to the agency’s records, the FDA
approves the vast majority of requests [3]. No data are available
concerning IRBs’ treatment of requests.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 05/22/15
For personal use only.
5.
No data are available concerning the total number of requests
for experimental drugs, who makes these requests, who
receives access, or how frequently the use of the experimental
agent in a compassionate use context was considered either a
success or a failure. With regard to the numbers of patients
seeking access to experimental drugs outside of clinical trials,
FDA data from 1 October 2013 to 30 September
2014 show that 1075 patients were granted access on the basis
of an undefined emergency need [1]. However, the FDA data
do not represent the total number of patient requests: requests
declined by either the drug’s manufacturer or the patient’s
physician would not be reported to the FDA. Additionally,
the FDA may approve programs, such as expanded access programs (EAPs) through which multiple patients may access an
experimental drug. The FDA would record this as one
decision.
While most media coverage of compassionate use focuses
on terminally ill patients, patients who are not terminally ill
but who are suffering with no relief from available treatments
(e.g., migraines, Lyme disease) or who face a degenerative process for which no cure exists (e.g., macular degeneration, multiple sclerosis) also seek to try experimental drugs. Their
numbers are also unknown.
How do patients access experimental
drugs?
4.
Ideally, patients who wish to try an experimental drug should
do so in a clinical trial. In a trial, outcomes, including adverse
events, are monitored, problems identified, and, should the
need arise, treatment provided to address side effects or other
adverse events. However, for a variety of reasons, not all
patients are eligible or willing to participate in a clinical trial.
Some companies offer EAPs through which patients can
access an experimental drug. These patients have data
collected that are of use to the company but often the amount
of data is less than in a clinical trial and there is no possibility
of the patient receiving a placebo.
Outside of clinical trials and EAPs, there are provisions
made for emergency use of experimental drugs for individual
patients. In these situations the focus is solely on saving the
patient, not on gathering data for drug development. Indeed,
given the fact that these patients are often in extremis, drug
1276
Brief historical overview
Patients have demanded access to experimental drugs outside
of clinical trials especially since the AIDS epidemic [4,5].
Indeed, programs to allow patients such access gained the
moniker of ‘compassionate use’ for the reason that they were
understood as a compassionate reaction to the fact that people
were dying from a generally untreatable disease (AIDS) faster
than scientific protocols of the day were able to offer solutions
or even grounds for much hope of a cure. Taking their cue
from AIDS activists, cancer activists began pressuring pharmaceutical companies to make experimental drugs available
to those who were unable or unwilling to participate in clinical trials. These activists scored a number of victories in which
companies set up compassionate use programs [6-8].
In 2001, 21-year-old cancer patient Abigail Burroughs,
who had run out of conventional treatment options, was
informed of two investigational drugs that might be of use
to her: Imclone System’s C225 (Erbitux) and Astra Zeneca’s
Iressa. Abigail, her family, and her supporters lobbied the
companies to make these drugs available; however, Abigail
died in mid-2001. Her family founded the Abigail Alliance,
an organization devoted to “helping create wider access to
developmental cancer drugs and other drugs for serious lifethreatening illnesses” [9]. The Abigail Alliance sued the FDA
leading, in 2007, to a federal court of appeals ruling that
affirmed FDA’s authority and found no right to access an
investigational drug [10].
6.
Current reforms
In the US, trade groups, patient advocates, state and national
legislators, and the FDA are all weighing in on the practice of
allowing patients who are not participating in clinical trials
access to medical products that have not yet been approved
for use or sale. In 2014, the Biotechnology Industry Organization (BIO) released a statement in which it promised that its
Bioethics Committee would “continue to work on developing
a better path forward for all parties involved in” compassionate use cases [11]. Likewise, the Pharmaceutical Research and
Manufacturers of America (PhRMA) released a policy to
take effect on 1 June 2015 proclaiming its commitment “to
continuing its work with patients, patient advocacy groups,
regulatory authorities, healthcare practitioners, academia and
Expert Opin. Pharmacother. (2015) 16(9)
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 05/22/15
For personal use only.
Should patients in need be given access to experimental drugs?
policymakers, to help ensure that there are appropriate and
targeted regulatory approaches to accelerate the development
and availability of innovative new medicines for patients” [12].
At present, 17 states have passed the so-called ‘Right to Try’
laws, and many others are considering similar legislation.
These laws claim to facilitate terminally-ill patients’ ability
to access experimental drugs by removing the requirement
for FDA and IRB approval. These laws are controversial on
many grounds, including both the inability of states to legislate about federal matters and whether these laws accomplish
anything other than the creation of false hope [13,14].
There are many questions about the laws themselves [15-18].
They contain no language requiring manufacturers to provide
products: thus, a patient’s ‘right’ to access pertains only to
freedom from interference from the FDA. Furthermore, these
laws require only that experimental products have completed
Phase I safety testing: thus, they offer no promise that the
treatments will be effective or truly safe in an ill patient. To
date, no patient has received access to a drug via right to try
legislation that was not already available under the preexisting expanded access policies. Despite these flaws, right
to try bills are popular, gaining the support of legislators,
the media, and many patient advocacy groups.
On the federal level, US Congressman Michael McCaul
(R-Texas) introduced H.R. 5805, the Andrea Sloan Compassionate Use Reform and Enhancement (CURE) Act, which
would reform certain aspects of compassionate use [19].
Among other reforms, this act would require the manufacturers of certain types of drugs to make their compassionate
use policies publicly accessible; it would require the government to collect and analyze certain information concerning
which patients requested and received compassionate use;
and it would create an expert body to evaluate compassionate
use.
Finally, within the FDA there have been changes with
regard to compassionate use. In February 2015, the agency
announced that an internal working group had revised the
paperwork necessary to request compassionate use. Right to
try advocates claimed that it took physicians approximately
100 h to complete the paperwork, ignoring reports of many
cases in which the timeline from request to decision was
made in hours [20]. After the paperwork revision, the FDA
announced that the new form ought to be able to be completed in 45 min [20,21].
7.
Societal considerations
Although healthcare providers are obligated to focus on the
well being of their patients, they also have a vested interest
in the development of new drugs that will benefit not only
current patients but also new generations of patients. Deciding whether to allow patients who may benefit from experimental drugs to access them must be done cautiously in
order to not slow the approval of new drugs. A negative outcome in a compassionate use context may result in the
abandonment of an experimental drug, in the requirement
of additional testing of the drug, or in the financial crippling
of the company developing the drug. While the FDA has
repeatedly stated that adverse events in compassionate use
contexts will not be held against a drug when it comes up
for approval, pharmaceutical companies are skeptical of this
claim, making them reluctant to provide access to their experimental drugs. Successful outcomes in compassionate use also
pose a risk to drug development in that patients may opt to
try to get access to a drug through compassionate use rather
than by enrolling in clinical trials.
All agree that patients seeking an experimental drug need to
have made an informed, voluntary decision. But, many
patients suffer from the therapeutic misconception, the mistaken belief that research is curative or at least helpful, when
the very opposite is sometimes true. Unless a neutral party
like an IRB or ethics committee is involved in reviewing consent procedures, it is hard to see how true consent will be
achieved.
8.
Expert opinion
When a tragic story about a desperate patient makes headlines, the American public looks to castigate some entity to
for failing to rescue the individual. The two most common
scapegoats are the FDA and drug companies. Americans are
keen to rescue those who find themselves in dire straits, and
they have supported social media campaigns intended to pressure drug companies into granting access to experimental
drugs. Yet this kind of support for patients is situational, often
strong when the ‘innocent victim’ is a child but weaker when
the patient is older, not photogenic, perceived as morally
flawed, or seen as contributing to their own illness [22].
While pharmaceutical companies insist that the FDA plays
a vital role in both drug development and patient protection,
right to try laws are premised on the idea of removing the
FDA from compassionate use decisions. At the same time,
when a company articulates the needs of future patients as a
rationale for focusing company resources (time, money, and
manpower) on moving an experimental drug toward FDA
approval rather than running a compassionate use program,
this argument is given short shrift and often dismissed as
self-serving or callous by a skeptical media and disbelieving
public [23].
Americans believe in rescue, whether that means providing
for emergency department care for everyone or seeking to free
miners trapped in a mine collapse, a child trapped in a well, or
a hiker stuck on a mountaintop. If rescue, even when costly
and against long odds, is an important moral value of our
society, then society must ensure that access to rescue is fair,
transparent, and affordable by those in need. At the moment,
access to investigational products is available only to the lucky
few who know about it, can draw attention to their plight,
navigate the process of requesting it, and who are given access
by drug companies, either by the company’s own decision or
Expert Opin. Pharmacother. (2015) 16(9)
1277
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 05/22/15
For personal use only.
A. L. Caplan & A. Bateman-House
as a result of pressure brought by an advocacy campaign or
powerful person. But who is truly deserving, what right they
have to obtain experimental drugs, how this access will be
paid for and monitored, who will be accountable for vetting
the merit of such requests, and how to balance the claims of
current and present patients against future patients remain
unresolved despite the enactment of right to try laws and
other efforts to reform compassionate use.
Given a lack of either societal or professional consensus
about how best to handle the allocation dilemma at the heart
of compassionate use, procedural protections become very
important. Providers must seek to inform their patients about
the availability of experimental treatments to the best of their
ability, making clear that both benefit and harm could result.
Legislators and others involved in rule-making must look at
right to try and other policies and ensure that they protect
potentially vulnerable patients from therapeutic misconception, overly eager researchers, and con artists looking to
exploit the desperate for personal profit. All stakeholders
must also devote themselves to addressing the special issues
raised by populations such as those unable to make their
own decisions on account of age or disability. Common sense
protections may include requiring second opinions of experimental recommendations, while policies that would maximize
equity may address such issues as granting non-terminally ill
patients the same access to experimental medications as terminally ill patients.
Compassionate use decisions will be made on an array of
factors such as disease entity; anticipated outcome with and
without the experimental agent; degree to which the experimental agent has been tested [24]; and the cost and/or availability of the experimental agent. At present, it seems
impossible to formulate an ethical one-size fits all policy.
The best path forward is to devote attention to concerns about
fair access, mitigating costs, ensuring informed consent,
vetting proposed remedies and those offering them, and
broadening access without destroying the current regulatory
system which guarantees the safety and efficacy of drugs and
interventions for all now and in the future.
Declaration of interest
AL Caplan and A Bateman-House serve as non-voting, nonpaid chair person and deputy chairperson of the compassionate Use Advisory Committee (CompAC), an external, expert
panel of internationally recognized medical experts, bioethicists, a patient representative formed by NYU School of Medicine, which advises the Janssen division of Johnson and
Johnson about requests for compassionate use of some its
investigational medicines. The authors have no other relevant
affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript
apart from those disclosed.
Bibliography
1.
Expanded Access Submissions Receipt
Report Oct 1, 2013-Sep 30,
2014. Available from: http://www.fda.gov/
downloads/Drugs/
DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/
DrugandBiologicApprovalReports/
INDActivityReports/UCM430188.pdf
2.
This is not the case in the 17 states that
have passed so-called “Right to Try”
laws, which will be discussed elsewhere in
this editorial
3.
For the most recent numbers from the
FDA, see Expanded Access Submissions
Receipt Report Oct 1, 2013- Sep 30,
2014. Available from: http://www.fda.
gov/downloads/Drugs/
DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/
DrugandBiologicApprovalReports/
INDActivityReports/UCM430188.pdf
4.
1278
Buhles WC. Compassionate use: a story
of ethics and science in the development
of a new drug. Perspect Biol Med
2011;54(3):304-15
5.
6.
7.
8.
9.
Darrow JJ, Sarpatwari A, Avorn J, et al.
Practical, legal, and ethical issues in
expanded access to investigational drugs.
N Engl J Med 2015;372:279-86
See, for example, United States,
Congress. House, Committee on
Government Reform. Compassionate Use
of Investigational New Drugs: Is the
Current Process Effective?: Hearing
before the Committee on Government
Reform, House of Representatives 107th
Congress, 1st Session, June 20, 2001.
U.S. Government Printing Office; DC,
USA: 2002
Burke MC. Oncology compassionate use,
single patient exemptions and expanded
access: a discussion of policies and
programs. Masters thesis, Massachusetts
College of Pharmacy and Health Sciences
2002
Bazell R. Her-2: the making of
herceptin, a revolutionary treatment for
breast cancer. Random House; New
York, NY, USA: 1998
The Abigail Alliance mission. Available
from: www.scotusblog.com/archives/07-
Expert Opin. Pharmacother. (2015) 16(9)
444-cb.pdf [Last accessed 28 March
2015]
10.
Abigail Alliance v. von Eschenbach,
495 F.3d 695 (D.C. Cir. 2007).
Available from: www.scotusblog.com/
archives/07-444_ob.pdf
11.
Biotechnology Industry Organization.
BIO statement on compassionate use
2014. Available from: https://www.bio.
org/articles/bio-statement-compassionateuse
12.
PhRMA. Principles on conduct of
clinical trials communication of clinical
trials results. Available from: http://www.
phrma.org/sites/default/files/pdf/042009_
clinical_trial_principles_final_0.pdf [Last
accessed 29 December 2014]
13.
Drug and Device Law. On “right to try”
legislation. 2014. Available from:
http://druganddevicelaw.blogspot.
com/2014/10/on-right-to-try-legislation.
html
14.
Gorski D. “Right to try” laws and dallas
buyers’ club: great movie, terrible for
patients and terrible policy.
Science-Based Medicine
Should patients in need be given access to experimental drugs?
2014. Available from: http://www.
sciencebasedmedicine.org/right-to-trylaws-and-dallas-buyers-club-great-movieterrible-public-policy/
15.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 05/22/15
For personal use only.
16.
17.
Caplan A. Right-to-try laws do nothing
to pay for unapproved drugs. Iowa City
Press-Citizen 2014. Available from:
http://www.press-citizen.com/story/
opinion/editorials/2014/08/20/right-trylaws-nothing-pay-unapproveddrugs/14302827/
Bateman-House A, Caplan A. Drug-right
bills give patients false hope. Philadelphia
Inquirer 2014. Available from:
http://www.philly.com/philly/
opinion/20141116_Drug-right_bills_
give_patients_false_hope.html
Bateman-House A. Are right to try laws a
good idea? National Coalition for Cancer
Survivorship 2014. Available from:
http://www.canceradvocacy.org/news/
guest-post-are-right-to-try-laws-a-goodidea/
18.
Wilkens RB. Is ‘right to try’ the right fit
for better access to investigational drugs?
IRB Advisor 2015;21-3
19.
Congressman Michael McCaul. Available
from: http://mccaul.house.gov/sites/
mccaul.house.gov/files/Andrea%20Sloan
%20CURE%20Act.pdf
20.
Lowes R. FDA to simplify
“compassionate use” drug applications.
Medscape Medical News
2015. Available from: http://www.
medscape.com/viewarticle/839292
21.
Gaffney A. From 100 Hours to 1:
FDA Dramatically Simplifies its
Compassionate Use Process, Regulatory
Affairs Professionals Society
2015. Available from: http://www.raps.
org/Regulatory-Focus/
News/2015/02/04/21243/From-100Hours-to-1-FDA-Dramatically-Simplifiesits-Compassionate-Use-Process/
22.
Kroll D. Rescuing Compassionate Use
from Social Media and Death Threats
2014. Available from: www.forbes.com
Expert Opin. Pharmacother. (2015) 16(9)
23.
Caplan A, Moch K. Rescue me: the
challenge of compassionate use in the
social media era. Health Affairs
2014. Available from: http://healthaffairs.
org/blog/2014/08/27/rescue-me-thechallenge-of-compassionate-use-in-thesocial-media-era/
24.
Caplan A, Plunkett C, Levin B. Selecting
the right tool for the job. Am J Bioeth
2015;15(4):1526-32
Affiliation
Arthur L Caplan†1 PhD &
Alison Bateman-House2 PhD MPH MA
†
Author for correspondence
1
William F and Virginia Connolly Mitty Chair,
Director,
NYU Langone Medical Center, Division of
Medical Ethics, New York City, NY, USA
Tel: +1 646 501 2514;
Fax: +1 646 501 2830;
E-mail: Arthur.Caplan@nyumc.org
2
Rudin Postdoctoral Fellow,
NYU Langone Medical Center, Division of
Medical Ethics, New York City, NY, USA
1279