JOURNAL OF PALLIATIVE MEDICINE

Volume 13, Number 12, 2010 Special Report

ª Mary Ann Liebert, Inc.
DOI: 10.1089/jpm.2010.0261

A Strategy To Advance the Evidence Base

in Palliative Medicine:
Formation of a Palliative Care Research Cooperative Group

Amy P. Abernethy, M.D.,1,2 Noreen M. Aziz, M.D., Ph.D., M.P.H.,3 Ethan Basch, M.D.,4 Janet Bull, M.D.,5
Charles S. Cleeland, Ph.D.,6 David C. Currow, B.Med., M.P.H.,7,8 Diane Fairclough, Dr.P.H.,9
Laura Hanson, M.D., M.P.H.,10 Joshua Hauser, M.D.,11 Danielle Ko, MBBS, L.L.B.,12 Linda Lloyd, Dr.P.H.,13
R. Sean Morrison, M.D.,14 Shirley Otis-Green, M.S.W., LCSW, ACSW, OSW-C,15 Steve Pantilat, M.D.,16
Russell K. Portenoy, M.D.,17 Christine Ritchie, M.D.,18 Graeme Rocker, M.D.,19
Jane L. Wheeler, MSPH,1 S. Yousuf Zafar, M.D., M.H.S.,1 and Jean S. Kutner, M.D., MSPH20

Abstract
Background: Palliative medicine has made rapid progress in establishing its scientific and clinical legitimacy, yet
the evidence base to support clinical practice remains deficient in both the quantity and quality of published
studies. Historically, the conduct of research in palliative care populations has been impeded by multiple
barriers including health care system fragmentation, small number and size of potential sites for recruitment,
vulnerability of the population, perceptions of inappropriateness, ethical concerns, and gate-keeping.
Methods: A group of experienced investigators with backgrounds in palliative care research convened to con-
sider developing a research cooperative group as a mechanism for generating high-quality evidence on prior-
itized, clinically relevant topics in palliative care.
Results: The resulting Palliative Care Research Cooperative (PCRC) agreed on a set of core principles: active,
interdisciplinary membership; commitment to shared research purposes; heterogeneity of participating sites;
development of research capacity in participating sites; standardization of methodologies, such as consenting
and data collection/management; agile response to research requests from government, industry, and investi-
gators; focus on translation; education and training of future palliative care researchers; actionable results that
can inform clinical practice and policy. Consensus was achieved on a first collaborative study, a randomized
clinical trial of statin discontinuation versus continuation in patients with a prognosis of less than 6 months who
are taking statins for primary or secondary prevention. This article describes the formation of the PCRC,
highlighting processes and decisions taken to optimize the cooperative group’s success.
1
Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
2
Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, North Carolina.
3
Division of Extramural Activities, National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland.
4
Health Outcomes Group, Memorial Sloan-Kettering Cancer Center, New York, New York.
5
Four Seasons, Flat Rock, North Carolina.
6
Department of Symptom Research, Division of Internal Medicine, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.
7
Department of Palliative and Supportive Services, Division of Medicine, Flinders University, Bedford Park, South Australia, Australia.
8
Southern Adelaide Palliative Services, Repatriation General Hospital, Daw Park, South Australia, Australia.
9
Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, Colorado.
10
Division of Geriatrics, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina.
11
Palliative Care and Home Hospice Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
12
Division of General Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts.
13
San Diego Hospice and The Institute for Palliative Medicine, San Diego, California.
14
Mount Sinai School of Medicine, New York, New York.
15
Division of Nursing Research and Education, City of Hope National Medical Center, Duarte, California.
16
Palliative Care Program, Division of Hospital Medicine, Department of Medicine, University of California, San Francisco, California.
17
Department of Pain Medicine and Palliative Care, Beth Israel Medical Center, New York, New York.
18
Birmingham-Atlanta VA Geriatric Research Education and Clinical Center and the Division of Gerontology, Geriatrics, and Palliative
Care, University of Alabama at Birmingham, Birmingham, Alabama.
19
Divisions of Respirology and Palliative Medicine, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
20
Division of General Internal Medicine, Department of Medicine, University of Colorado Denver School of Medicine, Denver, Colorado.
Accepted July 7, 2010.

1407
1408 ABERNETHY ET AL.

Introduction ment processes, have yet to be instituted across palliative care

organizations interested in research. Researchers must battle
Methodologically rigorous palliative
various antiresearch attitudes in palliative care, such as a belief
care research is needed
that research is incompatible with the goals of care.12,13

E xtensive research activity has followed the recogni-

tion of palliative medicine as a subspecialty; citation
trends and new publication channels reflect this collective
Additionally, palliative care is inherently interdisciplinary
and multidisciplinary; in practice, it entails collaboration
among specialists in medicine, nursing, chaplaincy and spir-
effort. Between 1970 and 2005, there has been a fourfold in- itual care, psychology, social work, and medical ethics, as well
crease in palliative care studies as a proportion of all Ovid as coordination across settings ranging from inpatient (hos-
MEDLINE citations (0.1% versus 0.4%). Palliative care clinical pice, hospital) to outpatient (home, clinic, assisted living fa-
trials comprised 1% of all palliative care literature in 1970; this cility, nursing home). This complexity introduces challenges
percentage rose to 7% during 2001–2005. Palliative care clin- into the conduct of research, such as the need to coordinate
ical trials as a percentage of all clinical trials rose from 0.2% in differing research approaches, venues for data collection, and
1970 to 0.8% in 2001–2005.1 The International Association of regulatory bodies. Finally, funding for palliative care research
Hospice and Palliative Care website now lists 38 journals is scarce; federal investment is low, and palliative care grant
specifically dedicated to hospice, palliative, and end-of-life applications are thought to be poorly received and/or not
care2; increasingly, palliative care-relevant articles are pub- fully understood by NIH study sections.14
lished in general medical, nursing, and social work journals.
Despite a greater volume of published palliative care
Cooperative groups in oncology
studies, the majority of palliative care evidence is not derived
from randomized controlled trials or other methodologically The cooperative group model, in which investigators work
rigorous studies. While it is possible that other study designs together to conduct large-scale trials in multi-institutional
are more appropriate to the palliative care setting, most pal- settings, may help overcome recognized barriers to research
liative care articles report case series or nonrandomized trials, in palliative care. In oncology, cooperative groups have
creating an imbalance in the sorts of research conducted in demonstrated remarkable success but they have also come
this field. A study examining palliative care research articles under intense scrutiny; a recent IOM report drew attention to
published from 2003–2005 identified 388 original articles, 8% inefficiencies in and challenges faced by the National Cancer
of which were randomized controlled trials (RCTs) and 2% of Institute (NCI)-sponsored cooperative groups.15 Both the
which were controlled clinical trials.3 successes and the shortcomings of existing cooperative
Prominent entities, such as the Institute of Medicine (IOM)4,5 groups provide insights to inform future, collaborative, pal-
and National Institutes of Health (NIH),6 have recommended liative care research.
that palliative care research become a national priority in Potential for success through the cooperative group model
the United States. Many opportunities remain, however, to is perhaps best illustrated in pediatric oncology. The NCI has
improve the evidence underlying clinical practice in palliative funded cooperative groups in this area since 1956; in 2000,
care and thus to provide more effective patient care. Multiple four groups merged into a single Children’s Oncology Group
studies have shown that critical outcomes in palliative care— (COG). The dramatically improved outcomes for childhood
for example, pain control—have not improved.1,7,8–10 Poor cancer patients— with overall 5-year survival rates increasing
symptom control may result from inadequacies in care delivery from less than 30% in the 1960s to nearly 80% by the late
and/or from ineffective clinical management; a more solid 1990s16,17—can largely be attributed to the aggressive, coor-
evidence base and an effective knowledge translation strategy dinated approach of the COG and its predecessors.18 By 1996,
should remediate this problem. pediatric cancer clinical trials cooperative groups provided
access to latest treatment protocols for nearly 95% of Ameri-
can cancer patients under the age of 15.19 With the COG’s
Perceived barriers to palliative care research
addition of an enhanced remote data entry system, enrollment
Multiple barriers have deterred clinical trials in palliative in COG clinical trials increased by 40%; in 2005, almost 90% of
care. The population is vulnerable due to symptom and dis- the more than 11,000 newly diagnosed patients registered at
ease burden, psychological and social stressors, and condi- COG institutions were enrolled in a COG clinical trial.20
tions impairing capacity to consent; this vulnerability raises The NCI currently funds 10 cooperative groups to develop
ethical concerns as well as feasibility issues related to research and coordinate multi-institutional clinical trials, including the
conduct. Fragmentation of the health care system creates Cancer and Leukemia Group B (CALGB), Eastern Co-
problems related to loss to follow-up, data heterogeneity, and operative Oncology Group (ECOG), and American College of
nonstandardized procedures. Many provider sites are small Surgeons Oncology Group. Although the cooperative group
and community-based; although clinically proficient, they model is now well entrenched in oncology, its success in
lack resources, research-relevant skills, and substantial pop- streamlining adult cancer clinical trials is debatable. The 2010
ulations for recruitment. Clinicians and caregivers, perceiving IOM report mentioned above documented that the current
research as an intrusion on the sanctity of the end of life, often process of activating new Phase III clinical trials in NCI co-
‘‘shield’’ patients from research staff.11 operative groups averages more than 2 years, and of acti-
Standardized research methodologies are virtually nonexis- vating Phase I and II studies typically requires more than 500
tent in palliative care, a field which has historically pursued the days.15 Many trials, especially those that take longest to open,
‘‘art of medicine,’’ orienting itself more toward compassion than close after failing to reach accrual goals; of all NCI-funded
science; this false dichotomy has inhibited research. Uniform Phase I–III trials that opened and closed between 2000–2007,
research infrastructure, including data collection and manage- 40%–50% failed to meet minimal accrual goals.21 The report
PALLIATIVE CARE RESEARCH COOPERATIVE 1409

found the activation path within cooperative groups to be advance the evidence base in palliative care, with an eye to-
complex, requiring many steps not critical to actual conduct of ward developing a coordinated national research effort. In-
the study.22 formal conversations culminated in a 1½-day meeting of
To elucidate the barriers faced by cooperative groups, Dilts researchers interested in participating in the formation of a
et al.23 carefully examined their function using the CALGB as palliative care cooperative group. Possessing expertise in
a case study. They identified four types of administrative patient-reported outcomes, biostatistics, practice-based re-
barriers to trial activation in oncology cooperative groups: (1) search networks, social work, nursing, and psychology, par-
procedural barriers, referring to policies or required steps, ticipants represented diverse clinical organizations, the NIH,
e.g., that a cooperative group protocol be reviewed by an existing cooperative groups, and international palliative care
external agency; (2) structural barriers, created by organiza- research networks. All participants funded most of their own
tional design, e.g., sites performing research tasks in differing travel expenses; those unable to physically attend participated
orders; (3) infrastructural barriers, e.g., delays in protocol re- via teleconference. The meeting was held on the University of
view; and, (4) synchronicity barriers, i.e., requirements that Colorado Denver Anschutz Medical Campus, January 16–17,
multiple steps come together before the study be launched.23 2010. Its purposes were to: (1) define the structure and func-
In subsequent work, Dilts and colleagues examined the pro- tion of a national interdisciplinary cooperative group in pal-
cess of Phase III clinical trial development in the ECOG and liative care research and (2) delineate an action plan for
identified 481 distinct process steps required for study acti- developing capacity for collaborative comparative effective-
vation. Trial activation required a mean of 783 days from ness research in palliative care.
executive approval and 808 days from initial conception.
Study development represented 44% of the total time neces- Funding
sary for Phase II trial activation, and 54% of that for Phase III
Financial support was provided by the National Palliative
trials. The most variable aspect of clinical trial development
Care Research Center.
was creation of study forms and preparation for data man-
agement, taking, on average, 401 days; compliance with
Results
common data elements added another 114 days.24
The COG highlights the potential contribution that coop- The meeting opened with a goal alignment exercise and
erative groups can make to scientific advancement and out- brainstorming session, followed by 16 brief presentations
comes improvement. Certain functions of cooperative groups, with question-and-answer periods (Table 1).
such as combining patient populations to more efficiently Participants unanimously agreed to form a research coop-
complete studies, make this structure well-suited to resolving erative group broadly focused on studies relevant to palliative
challenges encountered in palliative care research. The multi- care, called the Palliative Care Research Cooperative (PCRC).
disciplinary nature of palliative care, and the diversity of care Its mission is to decrease the burden of suffering and to im-
venues including community-based and home settings, pres- prove outcomes for patients with advanced life-limiting ill-
ent potential hurdles and care must be taken to avoid adding ness and their families. The group delineated core principles
layers of bureaucracy that slow the progress of research.24 that will guide PCRC development (Table 2).
Presentations by Australian and Canadian colleagues de-
Cooperative groups in palliative care scribed the experiences of two successful cooperative groups.
These individuals offered to share their organizations’ policies
Successful research cooperative groups with a palliative care
and structures (e.g., bylaws, forms, processes), so that the
focus exist in Australia (Palliative Care Outcomes Collabora-
experiences of established networks might inform PCRC de-
tive),25,26 Canada (Canadian Critical Care Trials Group),1,27
velopment. Development must address: processes, including
Europe (European Palliative Care Research Centre),28
those for adding new members, prioritizing research topics,
and Sweden (Palliative Care Research Network in Sweden
collaboratively developing a protocol, and initiating a clinical
[PANIS]).29 As yet, the United States does not have a palliative
trial; governance, including data ownership, data sharing,
care research cooperative group. The Population-based Pal-
and dispute resolution; standardization of research proce-
liative Care Research Network (PoPCRN),30 a hospice practice-
dures, e.g., through data collection forms, recruitment and
based research network centered at the University of Colorado
consenting protocols, inclusion of minorities and women, and
Denver, offers a precedent for a multisite network devoted to
standardized human subject protection; data management,
research in this field, though it has not regularly pursued
covering data collection, transfer, storage, quality assurance,
randomized clinical trials and lacks infrastructure for phar-
management, aggregation, and extraction; and analysis, in-
maceutical trials. A call to the discipline has underscored the
cluding statistical support and reporting. A set of PCRC op-
need for a U.S. cooperative group that can spark progress in
erating procedures will address these issues. The definition of
palliative care research similar to that of our international
members’ roles, and description of different levels of investi-
colleagues.12
gator and site involvement, represent additional topics for
This article describes the formation of a new palliative care
clarification.
research cooperative group, developed in light of the barriers
An initial PCRC membership, comprising all participants
to research in this field and the challenges and opportunities
in the Denver meeting, was agreed upon. Additional mem-
afforded by a cooperative group structure.
bers will be included to extend the reach of the network and
the availability of research infrastructure for palliative care
Methods
investigators. The PCRC will emphasize education through
From 2005–2010, a group of senior palliative care investi- mentoring junior investigators and helping to build skills
gators, methodologists, and clinicians discussed how best to among staff at research-naı̈ve clinical sites.
1410 ABERNETHY ET AL.

Table 1. Palliative Care Research Cooperative January 2010 Meeting Participants and Presentations

Name Institution Presentations

Amy Abernethy Duke University Medical Center Parallel stories from U.S. hospice and palliative care
(Host)a and lessons learned; Moving from outcomes to data
collection
Ethan Basch Memorial Sloan Kettering Cancer Center Adverse events as outcomes, or vice versa?
Janet Bull Four Seasons What does cooperative research require? And offer?
David Cella Northwestern University Medical Center
Charlie Cleelanda M.D. Anderson Cancer Center Current and previous initiatives for joint research in
palliative care and symptom management; out-
comes measurement in disadvantaged and under-
served populations
David Currowa Flinders University (Adelaide, Australia) Australian model for a palliative care clinical studies
collaborative
Diane Fairclougha University of Colorado Denver Medical
Center
Laura Hansona University of North Carolina, Chapel What does cooperative research require? And offer?
Hill
Josh Hausera Northwestern University Medical Center
Paul Hutson University of Wisconsin
Jean Kutner (Host)a Univ. of Colorado Denver Medical What makes a population-based research network?
Center
Linda Lloyda San Diego Hospice and The Institute for
Palliative Medicine
Janelle McCallum Denver Hospice
Jeri Millera National Institutes of Health
R. Sean Morrisona Mount Sinai School of Medicine National Palliative Care Research Center and The
Pepper Center
Ann O’Maraa National Institutes of Health A Brief History of the Oncology Cooperative Groups;
IRB Issues; National initiatives related to PRO’s and
other palliative care-related outcomes
Shirley Otis-Greena City of Hope City of Hope palliative care research and education

Steve Pantilat University of California at San Francisco

Russ Portenoy Beth Israel Medical Center
Christine Ritchiea University of Alabama at Birmingham Research at the UAB School of Medicine Center for
Palliative Care
Graeme Rockera Dalhousie University Canadian model for a palliative care clinical studies
collaborative

Jeff Sloana Mayo Clinic PRO Advances in Palliative Care

David Westa University of Colorado Denver
Jane Wheelera Duke University Medical Center
Yousuf Zafara Duke University Medical Center
a
Participated in-person vs. via videoconferencing.
IRB, Institutional Review Board.

Dilts et al. 23 underscored the importance of an early ‘‘win’’ cused on statins. Among the most prescribed medications in
for maintaining initial momentum and setting an enduring, the world, statins are commonly encountered in palliative
productive course for a cooperative group. PCRC founding care. Because more than 25% of Medicare beneficiaries take a
members therefore decided to launch the PCRC with a dem- statin,33 any change in prescribing practice could dramatically
onstration clinical trial that is straightforward to implement impact health resource utilization. While the benefit of statins
and possible to complete within a short timeframe—but also for patients with cardiovascular risk, but without a defined
likely to definitively answer an important clinical question. short survival prognosis, is well-demonstrated,34–36 the ben-
The group chose discontinuation of medications for comorbid efit versus cost/risk of this medication in patients with an
chronic disease, among patients with advanced life-limiting estimated prognosis of less than 6 months remains unknown.
illness, as a compelling and clinically meaningful issue, one Statins can contribute to illness burden. Up to 8% of patients
arising frequently in practice, and one for which genuine taking statins report gastrointestinal side effects37; myopathy
clinical uncertainty exists. is the most common serious adverse effect.35,38,39 Conversely,
The first trial, envisioned as a step toward operationalizing the safety of statin discontinuation is a critical concern; ob-
a theoretical framework for managing comorbid illnesses at servational studies suggest that 1-year mortality may be
the end of life,31,32 is a medication discontinuation trial fo- higher in acute myocardial infarction survivors whose statins
PALLIATIVE CARE RESEARCH COOPERATIVE 1411

Table 2. Palliative Care Research Cooperative Group Core Principles

 Active interdisciplinary membership, with an understanding that membership decisions will reflect an inclusive rather than
exclusive orientation.
 Commitment to shared research purposes, including development of meaningful and sustainable palliative care research,
patient-focused inquiries and methods, and use of measurable outcomes valued by patients, investigators, regulators, and
funders.
 Heterogeneity of sites, i.e., participation of sites with diverse skills, demographics, practice patterns, and healthcare delivery
systems, to ensure the PCRC’s ability to meet the needs of diverse research studies.
 Development of research capacity in participating sites, to upskill sites through increasing their knowledge of research
methodology.
 Standardization of methodologies, such as study procedures, consenting, and data collection and management.
 Agility, i.e., ability to respond efficiently to requests of investigators, government sponsors, and industry.
 Responsiveness to regulatory and ethical requirements, including human subject protections.
 Focus on translation, i.e., connecting innovative ideas with clinically relevant and measurable outcomes; rapid
implementation of research results to effect change.
 Engagement in education, to energize and train future researchers in palliative care.
 Generation of actionable results that can inform health policy.

PCRC, Palliative Care Research Cooperative.

are discontinued.40 The effect of statin discontinuation on value to the protocol; inclusion of operational complexity,
other outcomes important in palliative care, such as patient alongside scientific merit, in study review criteria, and; re-
burden, quality of life, and performance status, is also unclear. ducing study activation time through changes to concept or
Although an enlarging literature, predominantly in palliative protocol. Because studies that fare poorly on initial scientific
care journals, supports discontinuation of medications, spe- review exhibit disappointing long-term success, they suggest
cifically statins, in end-stage disease,41 the balance of medi- winnowing out these unlikely-to-succeed projects in favor of
cation efficacy versus burden has yet to be defined in clinical other, potentially more productive, endeavors. A focus on
studies. practicality, feasibility, and efficiency is key to timely com-
With statin discontinuation as the agreed topic for a PCRC pletion of collaborative studies.
demonstration trial,32 members worked together to develop Overall, palliative care is ripe for research development but
an application for a federal grant, submitted to the NIH in under-resourced for research infrastructure and not savvy in
March 2010; the National Institute of Nursing Research has research processes. Hence, a PCRC data collection strategy
awarded funding. must be pragmatic, inexpensive, and convenient in commu-
nity-based as well as academic settings. To allow for partici-
Discussion pation of smaller and nonacademic sites, total costs of
research need to be minimized through choice of study design
The need for a concerted approach to evidence develop- and methodology; funding will likely need to be secured from
ment in palliative care is well accepted. What has been less the NIH, to sufficiently support infrastructure development
clear is the best way to develop that evidence base given the and studies. Care should be taken to identify best items, in-
barriers to research in palliative care, disparate pockets of struments, measures, and outcomes – matched to the research
research expertise, and a majority of clinical sites not con- question and to practical considerations. By incorporating
versant with research processes. A cooperative group frame- expertise in patient-reported outcomes at the outset, the
work may help overcome many obstacles to palliative care PCRC is making a commitment to research that directly ad-
research, such as lack of standardized definitions and pro- dresses the concerns of people with complex and/or life-
cesses, small populations in clinical trial sites, and uneven limiting illness. The most consistent hurdle to palliative care
distribution of expertise. clinical trials is participant recruitment; hence, the first PCRC
Cooperative groups have met with varying levels of suc- trial will incorporate a careful recruitment program based
cess. The PCRC is endeavoring to learn from the experiences upon prior successful models in palliative care.42 Other con-
of other cooperative groups. Likely to support its success are: cerns requiring careful attention are participant burden,
the coalescence of a sizeable group of committed, experienced clarity of outcomes, data management, missing data, and
investigators who have a history of and commitment to ethical issues.
working together; agreement on the cooperative group’s Challenges that may limit the success of the PCRC group
purposes, parameters, and first steps; a pragmatic approach approach include: (1) its inherent risk, in that we cannot know
focused on prioritizing studies and efficiently generating re- in advance if the PCRC is a feasible structure; (2) the possi-
sults that can be applied to current clinical practice, and; a bility that unique vulnerabilities of the population and human
design intended to support learning-through-doing and iter- subjects protections concerns may limit feasibility of a multi-
ative adaptation. Streamlining research activation processes site approach; (3) the possibility of lack of funding; (4) the
and minimizing the layers of bureaucracy will help to avoid possibility that only large research institutions will partici-
the roadblocks and delays encountered by other cooperative pate, thereby potentially limiting the generalizability of re-
groups. Dilts et al.23,24 suggest several procedures for over- sults, failing to build research capacity more broadly, and
coming barriers, which the PCRC plans to adopt: process omitting valuable perspectives from agenda setting and pri-
mapping, to identify and eliminate those steps that do not add oritization; (5) the need for strong leadership, balanced
1412 ABERNETHY ET AL.

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consulting funding (less than $10,000) from Helsinn and Pfi- Oncology Group Nursing D: Creating a novel structure for
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