Characterizing expanded access and compassionate use programs for experimental drugs
Miller et al. BMC Res Notes
Characterizing expanded access and compassionate use programs for experimental drugs
Jennifer E. Miller 0 3
Joseph S. Ross 1 6 7
Kenneth I. Moch 5
Arthur L. Caplan 4
0 Division of Medical Ethics, Department of Population Health, NYU School of Medicine , 227 East 30th Street, Office 723, New York, NY 10016 , USA
1 Section of General Internal Medicine and Robert Wood Johnson Foundation Clinical Scholars Program, Department of Medicine, Yale School of Medicine , New Haven , USA
2 261 , Pittsburgh, PA 15203 , USA
3 Bioethics International , New York , USA
4 Division of Medical Ethics, Department of Population Health, NYU School of Medicine , 227 East 30th Street, Office 722, New York, NY 10016 , USA
5 Cognition Therapeutics, Inc. , 2403 Sidney St
6 Center for Outcomes Research and Evaluation, Yale-New Haven Health , 789 Howard Ave, New Haven, CT 06519 , USA
7 Department of Health Policy and Management, Yale School of Public Health , New Haven , USA
Objective: We sought to determine the characteristics of “expanded access” and “compassionate use” programs registered in ClinicalTrials.gov and to determine the percentage of drugs provided through these programs that ultimately received FDA marketing approval. Results: We identified 398 expanded access and compassionate use programs (hereafter referred to as expanded access programs) registered on ClinicalTrials.gov. Industry funded 61% (n = 241) of programs individually or collaboratively, while NIH and the US Federal Government rarely funded programs (3% [n = 11] and 2% [n = 6], respectively). Most programs provided access to drugs (71% [n = 282]), 11% to biologics (n = 43), and 10% to medical devices (n = 40). These programs covered 460 unique conditions, the most common being HIV (n = 26), leukemia (22), and multiple myeloma (n = 14). Only 2% of programs reported results in ClinicalTrials.gov. Most programs (82%) were open to enrolling adults and seniors (n = 326). These programs provided access to 210 unique experimental drugs, of which 76% have received FDA approval.
Compassionate use; Expanded access; Experimental drugs; Access to medicines; Ethics; Bioethics; Policy; Right to Try Laws; 21st Century Cures Act; Pharmaceutical industry; Real-world evidence
Proposed federal Right to Try legislation, advocated
by the White House, [
] allows physicians to prescribe
experimental therapies unapproved by the U.S. Food and
Drug Administration (FDA) to terminally ill patients.
Proponents say these laws, which have already passed
in 36 states, are vital to providing potentially lifesaving
therapies to terminally ill patients who do not qualify for
clinical trials. Critics contend patients can already access
experimental drugs through the FDA’s Expanded Access
Program, which grants 99% of requests but depends on
consent by medical product manufactures [
Expanded access programs, sometimes also called
“compassionate use” programs, provide patients with
serious or immediately life threatening diseases or
conditions access to investigational products outside of
clinical trials. Under the current Federal Food, Drug, and
Cosmetic Act (FD&C Act), patients seeking expanded
access generally need their physician to determine they
have no alternative available therapy and no access to a
clinical trial for their disease or condition. Additionally,
the patient’s treating physician must agree to apply for
expanded access on their behalf and the medical product
company must agree to provide the investigational drug
]. Currently, a company can decline a request or it can
approve the request, but is not obligated to provide the
drug for free [
Much of the scholarly literature on expanded access
programs focuses on the role of the FDA [
] or other
regulatory bodies  in providing patients access to
experimental drugs, or the ethics [
] and legal
aspects of these programs [
]. A few papers also
explore the role of social media and patient advocacy in
fostering pre-approval access [
]. Very few papers
provide empirical data or data-driven characterizations
of expanded access programs.
The main, perhaps only, empirical paper on expanded
access programs was published by the FDA. It details
how many expanded access requests it received over the
last ten years and their rate and handling of approvals
(99% of requests were approved) [
]. In general, the
literature provides little to no insight on the characteristics
of these programs or whether the provided experimental
drugs ever receive FDA approval.
Given the contentious debate surrounding the Right
to Try laws [
] and lack of empirical information about
expanded access programs in the literature, we sought to
determine the characteristics of “expanded access” and
“compassionate use” programs registered in
ClinicalTrials.gov, the trial registry maintained by the U.S. National
Institutes of Health (NIH). We also sought to determine
the percentage of drugs provided through these
programs that ultimately received FDA marketing approval.
We searched ClinicalTrials.gov to identify all expanded
access and compassionate use programs registered by
July 1, 2016. After identifying all relevant trials in the
ClinicalTrials.gov database using the search terms
“compassionate use” and “expanded access” we reviewed
trials manually for relevance and removed duplicate trials
(trials listed multiple times under the same NCT
number). ClinicalTrials.gov is a publicly available registry and
database maintained by the National Library of Medicine
(NLM) at the National Institutes of Health (NIH), created
in 1997 as a results of the Food and Drug Administration
Modernization Act of 1997 (FDAMA).
For each identified program, we abstracted the
program’s registration date, funding source, product type
(drug, biologic or device), condition treated, patient age,
number patients enrolled, whether the program was for a
single or multiple patients, and reporting of trial results.
For drugs only, we determined FDA approval rates by
cross-referencing the drug provided in the expanded
access program with Drugs@FDA. Drugs@FDA is a
public database maintained by the US FDA, listing most
drug products approved by the FDA since 1939. We used
descriptive statistics, such as means, proportions, and
medians, and all analyses were performed using
Microsoft Excel v2013 (Redmond, Washington).
We found 527 trials using our search criteria on
ClinicalTrials.gov. After removing 54 duplicate trials and 75
irrelevant trials, 398 programs met our final inclusion
criteria as compassionate use (CU) or expanded access
(EA) programs (hereafter referred to as expanded access
programs). Of these 398 programs, 306 were labeled as
expanded access only programs, 49 were compassionate
use only, and 43 programs used both terms. The
earliest recorded program started in June of 1989. It was for
“Compassionate use of tetrabenazine in the treatment of
abnormal movements,” sponsored by Baylor College of
Industry funded 61% (n = 241) of the 398 programs
individually or collaboratively. In contrast, the NIH and
the US Federal Government rarely funded programs
(3% [n = 11] and 2% [n = 6], respectively) (Table 1). 36%
of programs are classified as funded by an institution
“Other” than the Industry, NIH, or US Federal
Government. The “Other” category generally refers to university
or academic sponsors.
Most programs [71% (n = 282)] provided access to
drugs, 11% biologics (n = 43), and 10% medical devices
(n = 40). These programs covered 460 unique conditions,
the most common being HIV (n = 26), leukemia (22),
and multiple myeloma (n = 14). Most programs (82%)
were open to enrolling adults and seniors (n = 326).
Several registration fields lacked data. For example, 80%
didn’t indicate whether the program was single-patient
or multi-patient, 74% lacked phase data, and 98% had no
reported results (n = 390).
The FDA subsequently granted marketing approval for
drugs provided in 68% (n = 192) of expanded access
programs. These programs provided access to 210 unique
experimental drugs, of which 76% (n = 160 of 210) have
received FDA approval. We did not analyze FDA approval
rates for the biologics or devices.
Nearly 400 expanded access and compassionate use
programs were registered on ClinicalTrials.gov as of July
2016. Most programs were sponsored by medical
product manufacturers. This suggests that even without
federal Right to Try legislation, the pharmaceutical industry
is establishing programs to make experimental therapies
available to terminally ill patients.
Most (76%) provided drugs in expanded access
programs eventually received FDA approval. Thus, provided
drugs in registered expanded access programs are, more
times than not, eventually deemed safe by the FDA.
Notwithstanding, the fact that nearly 25% of expanded access
drugs have yet to receive FDA approval, shows that we
cannot entirely eliminate safety and efficacy questions in
expanded access and compassionate use programs.
It is reasonable to allow the FDA to retain its
oversight and approval role for these programs, in order to
help mitigate safety risks for patients- especially since
it approves 99% of expanded access and compassionate
use requests. Currently, patients wishing to gain access
to experimental drugs through compassionate use and
expanded access programs, must obtain FDA approval.
Proposed Right to Try Legislation generally removes this
step of needing FDA oversight and approval.
Legislative efforts should also aim to expand patient
access to clinical trials, which in some cases could
alleviate the need for expanded access and
compassionate use programs. Currently, clinical trial access is often
limited by several factors, including a patient’s location,
age, and health status [
]. Most clinical trials enroll
younger, healthier, and whiter patients than the
typical patient population [
]. The 21st Century Cures
Act makes some progress in expanding access to clinical
Expanded access programs raise broader ethical and
regulatory questions, including whether (and how much)
product manufactures should re-direct investigational
products and resources from formal clinical trials to
patients requesting expanded access and how to finance
these programs. In addition, experts are using [
advocating the use [
] of expanded access programs as
“real world evidence” for drug safety or efficacy. While
the reliability of using these data for this purpose is
debatable, it’s worth noting that, thus far, we found only
2% of programs reported results in ClinicalTrials.gov.
Important information about expanded access and
compassionate use programs was frequently missing from
ClinicalTrials.gov, limiting precise insight into exactly
which patients and how many are accessing
experimental agents. This limitation should decrease over time. The
FDA Amendments Act (FDAAA) final rule, released in
September 2016, newly requires expanded access
programs be registered on ClinicalTrials.gov and be kept
up-to-date. Thus, ClinicalTrials.gov should improve in
robustness over time for understanding U.S. expanded
FDA: U.S. Food and Drug Administration; FD&C Act: Federal Food, Drug, and
Cosmetic Act; NIH: U.S. National Institutes of Health; NLM: National Library of
Medicine; FDAMA: Food and Drug Administration Modernization Act of 1997;
FDAAA: FDA Amendments Act.
Dr. Jennifer Miller and Dr. Joseph Ross had full access to all data in the study.
Miller takes responsibility for the integrity of the data and the accuracy of the
data analytics. Study concept and design: all authors. Acquisition, analysis or
interpretation of data: all authors. Drafting of the manuscript: Miller. Critical
revisions of the manuscript for important intellectual content: all authors.
Study Supervision: Caplan. All authors read and approved the final manuscript.
Dr. Ross receives support through Yale University from Johnson and Johnson
to develop methods of clinical trial data sharing, from Medtronic, Inc. and the
Food and Drug Administration (FDA) to develop methods for post-market
surveillance of medical devices, from the Food and Drug Administration
(FDA) to establish the Yale-Mayo Center for Excellence in Regulatory Science
and Innovation (CERSI), from the Blue Cross Blue Shield Association to better
understand medical technology evaluation, from the Centers of Medicare and
Medicaid Services (CMS) to develop and maintain performance measures that
are used for public reporting, and from the Laura and John Arnold Foundation
to support the Collaboration on Research Integrity and Transparency (CRIT)
at Yale. Moch receives funding from Cognition Therapeutics, Inc. Dr. Caplan
receives support through NYU School of Medicine from Johnson and Johnson
to work on issues related to compassionate use and expanded access. Dr.
Miller receives funding from the Laura and John Arnold Foundation.
Availability of data and materials
The datasets generated and/or analysed during the current study are available
from the corresponding author on reasonable request.
Ethics approval and consent to participate
Consent for publication
No specific entity funded this research.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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