is director of clinical research at
Oregon Health & Science University's Knight Cancer
Institute and professor of healthcare management in the university's Division
of Management. He was also a member of the IOM committee that drafted the April
lengthy delays are not due to any one part of the approval process, but rather
because review of a protocol by one body, such as NCI or an institutional IRB,
can trigger feedback loops as a protocol is passed back and forth between the
investigators, the cooperative group, NCI, IRBs and FDA, sometimes for the sake
of relatively minor changes.
of these reviews are done in sequence rather than in parallel, and most of the
review questions and comments are transmitted in writing.
study, published in Clinical Cancer Research in November, went on to
show that the longer it takes to launch a trial, the less likely the study is
to reach patient accrual targets.
studies that took more than two or three years to even open, their success rate
of completion, because the science had changed, was very low," Doroshow said on
the Feb. 20 edition of
BioCentury This Week, BioCentury's public affairs television
incomplete study extends false hope to patients who expect their participation
in clinical trials will contribute to better treatments.
also have discouraged some industry sponsors from placing important trials at
the cooperative groups. This means the companies have less access to the
cooperative group's infrastructure and expertise, and that the cooperative
groups have less access to novel compounds - and to supplemental funding from
startup time, which has been extremely long, has played a role in determining
whether a sponsor would place an important study with cooperative groups," said
Peter Ho, co-founder and president of cancer company
BeiGene Ltd. "For industry, we'd like to get going in Phase II
in 4-6 months."
was previously VP of oncology development at
Johnson & Johnson, SVP of the Oncology Center of Excellence
in Drug Discovery (CEDD) at
GlaxoSmithKline plc and, in the 1990s, worked as part of NCI's
Cancer Therapy Evaluation Program (CTEP), a group within the Division of Cancer
Treatment and Diagnosis that oversees the cooperative groups.
Harper, SVP of global development and CMO at
Amgen Inc., agreed timelines influence decisions to place
studies with cooperative groups. "Major factors for deciding are timelines,
which can be very long," he told BioCentury.
does many studies with NCI and its cooperative groups, Harper said, but
generally not studies intended for registration unless they are measuring hard
either we use them as ways to screen different tumor types, which we would
follow up with Amgen-sponsored studies, or if measuring survival," he said.
that absolutely have to work, we do ourselves. Things that are more flexible,
or for large studies where you would compete with cooperative groups - or big
adjuvant studies, for example, that take seven years to do - make you lean
toward cooperative groups," he added.
agreed cooperative groups are ideal for some kinds of trials, such as studies
in rare tumors. "It takes a lot for a sponsor to put together a group of
investigators and sites. In the cooperative group, that mechanism, that
organization, might be set up already," he told BioCentury.
Parkinson, who has led several oncology R&D groups and also worked within
CTEP, concurred "there are certain types of trials only cooperative groups can
an example he cited adjuvant trials, "which have been very, very large
historically and long because of the endpoints, and essentially have not been
and probably should not be done by industry."
is now president and CEO of diagnostic company
Nodality Inc., and previously was SVP of oncology R&D at
Biogen Idec Inc., VP and head of oncology development at Amgen,
head of oncology at
Novartis AG, chief of NCI's Investigational Drug Branch and
acting associate director of CTEP.
he said the cooperative groups "involve the leading oncologists of any era,"
Parkinson said he would not likely entrust a key trial to them - "not if the
trial were integral to the survival of my company."
he told BioCentury, "I would not put my main registrational trial in a
cooperative group. I would consider secondary indication trials, or trials
helping to answer biological questions about which subgroups of patients are
Doroshow's initiatives, the groups have already reduced the time to activate
and open studies by 60%.
of the solutions have been surprisingly simple. One of the biggest changes, he
told BioCentury, was to insist on deadlines for every step of the process. He
also instituted the use of conference calls for investigators to respond to IRB
questions about protocols in real time instead of engaging in back-and-forth
saves literally months and costs nothing. In fact it saves money," Doroshow
also provided grant supplements so the groups could hire staff to ensure
deadlines are met.
deadlines and process changes went into effect April 1, 2010. Jan. 1 was the
first "drop-dead" date, the point at which any trial was to be dropped if the
cooperative groups had been working on it for two years but the study had not
yet been started.
three trials out of hundreds that could have been terminated were," Doroshow
goal is to be consistent with industry norms. "Another six months from now,
I'll know just how well we're hitting these early timelines," Doroshow said.
"It's been quite a year, and turn-around time to approval has gone from 120-140
days to 40 days."
next part of Doroshow's plan is the installation of a clinical trials data
management system that will be used by all the cooperative groups.
system will allow Internet-based patient enrollment and randomization,
replacing a paper-based process that is both tedious and error prone. It also
will function as a uniform collection system for clinical data from all sites
involved in a trial, with standardized case report forms.
of the most important things is to make it easy for both patients and for
participating physicians to participate," Doroshow said on BioCentury This Week.
"We hope soon to be able to put forward a national system for clinical trials
data management, an IT system that will be uniform across the country that will
allow investigators - whether they are in a private office or at an academic
medical center, no matter what the study is and who originated the study - to
have a standard approach to electronic data entry."
Desmond-Hellmann, chancellor of the
University of California, San Francisco and former president of
product development at
Genentech Inc., said a uniform IT system could improve both
efficiency and data quality, which is sometimes a bigger issue in cooperative
group trials than in industry trials.
the data "is a huge advance," she told BioCentury.
says reducing study timelines and implementing a unified data management system
alone will not be sufficient to improve efficiency and enable the groups to
incorporate more innovative science into their studies. That, the report said,
will require consolidating the cooperatives into a smaller number of groups, as
well as increasing their funding.
to the report, a smaller number of groups ideally would maintain strong
competition for trial concepts and help ensure that only the highest-priority
trials are undertaken.
according to IOM, there is no system for prioritizing the most important
studies, or those most likely to succeed.
has 10 disease-specific scientific steering committees charged with
prioritizing and refining concepts for Phase II and III trials to better
allocate resources, increase scientific quality and reduce duplication.
are steering committees for gastrointestinal, gynecologic, head and neck,
genitourinary, breast, thoracic and brain cancers, plus leukemia, lymphoma and
myeloma. Each one is composed of outside cancer experts and NCI senior
the committees do not rank trial concepts against each other.
IOM neither specified the ideal number of groups, nor indicated which should
merge or remain independent, the report did note: "Groups focused on a single
disease site or modality would likely need to merge with multidisciplinary
Groups under this system."
a presentation to the group chairs in November, Doroshow said NCI had
determined four adult groups and one pediatric group are the right numbers. The
ability to "prioritize molecular characterization resources and develop
molecularly driven trial designs" can "be achieved more easily with fewer
competing research organizations," according to slides from Doroshow's
presentation also said the planned IT system for clinical data management and
tissue resource management "will constantly require modification," which would
be "more manageable with fewer independent entities."
presentation did not say which groups might be the surviving entities, but did
suggest "scientific interactions around imaging" would be facilitated by
American College of Radiology Imaging Network (ACRIN) into a
"setting with more access to patient resources for investigational studies."
Liu, associate professor of medicine and oncology in the Lombardi Cancer Center
Georgetown University, is a proponent of consolidation. "What
will be key is how the groups realign. Not every group is structured in the
same way, and their talents are different. Combining groups with different
strengths may foster better ideas," she suggested.
you took a surgical group - hypothetically speaking - and merged it with one of
the larger oncology groups, we could increase the number of meaningful
collaborations between medical oncology, surgery and radiation medicine," Liu
is the principal investigator forCancer
and Leukemia Group B (CALGB) at Georgetown and a member of
CALGB's breast cancer committee, correlative science subcommittee, executive
committee and data audit committee. She also was a member of the IOM committee
that drafted the April report.
argued that revamping the system to function as a truly national network is
essential to bolstering the cooperatives' ability to incorporate modern tools
of molecular oncology.
think in the future we will have to have a system beyond what most pharmas can
do, that can screen thousands of patients, that has 2,000 sites up, ready and
ongoing, that will allow us to find the next ALK inhibitor," he told
3-5% of non-small cell lung cancer (NSCLC) tumors are anaplastic
lymphoma kinase (ALK)-positive.
we are going to cure lung cancer 3% at a time, we need access to sites, science
and systems that can find patients and pilot these ideas, and to work with
pharma to do it," Doroshow said.
Parkinson agreed. "Industry is giving lip service to biomarkers, usually
against conventional indications, because they believe that's what regulators
want to see," he said. "But there's no better way to identify subsets than
cooperative group trials, because they have all the basic science, pharmacology
and clinical investigators."
problem, Parkinson said, is "the groups are slow and ponderous and don't have
the resources to do the biological characterization that's necessary for more
appropriate and efficient characterization of patients."
Hait, global therapeutic area head for oncology R&D at J&J, also
cautioned that the cooperative groups will need more than streamlined
operations and additional funding to perform biomarker research with the rigor
that would be required to support registration.
a huge education issue at the site level, how specimens are harvested,
annotated, etc. The cooperative groups are good at rounding up
paraffin-embedded specimens. But for many tests you need not only
paraffin-embedded biopsies, but biopsy samples that are frozen and handled in
different ways," he told BioCentury.
has made it plain it does not intend to foist a specific consolidation plan
onto the cooperative groups, preferring instead to let the group chairs work it
out. But while the chairs' initial response to IOM recommendations was
favorable, resistance has since bubbled up.
a public comment on the IOM report issued last September by the Coalition of
Cancer Cooperative Groups, nine of the group chairs said they have begun to
take steps to improve operational efficiency. They cited adherence to the new
timelines and the planned adoption of a common data management system as
of the groups, ACOSOG,
North Central Cancer Treatment Group (NCCTG) and CALGB, were
already discussing consolidating their biostatistical and data management
centers before the IOM report came out, and that consolidation is now well
chairs added: "An internal dialogue is underway to address the optimal
configuration of our scientific programs and portfolios, building on our
diversity and strengths."
comment was signed by all the group chairs except Laurence Baker of
SWOG. Baker declined to be interviewed for this story, but
group spokesperson Frank DeSanto confirmed SWOG is not currently discussing a
merger with any of the other cooperative groups.
Gynecologic Oncology Group chair Philip DiSaia issued a white
paper arguing GOG should not be merged with any other groups.
argument was predicated on GOG's unique focus, its accomplishments in clinical
and translational research, and differences in the practice of gynecologic
oncology compared with other cancer disciplines.
study of gynecologic cancers has been attempted by Groups other than the GOG.
In point of fact, SWOG has attempted to accomplish this on two occasions
without success, and ECOG's attempt in this area also was unsuccessful," the
white paper noted.
warned: "Should the spirit and integrity of the GOG be disrupted by attaching
portions to various large medical oncology groups, the outcome will be repeated
Eastern Cooperative Oncology Group (ECOG) and SWOG are the two
largest cooperative groups.
told BioCentury he fears merging into a larger group will limit the number of
gynecological studies that get approved. "SWOG, for instance, has a quota on
how many protocols the myeloma committee can develop and how many leukemia can
develop. We believe we would be compromised on the number of ideas we could
pursue," he said. "Now, we go for the important ideas, and when we don't have
the money, we go get it from industry."
according to DiSaia, "none of the big groups want us, and NCI doesn't want us
to join them anyway. That leaves the radiation oncology group, NSABP, ACRIN -
it's like oranges, apples, kumquats and plums. At least when you merge banks,
they're both banks," he said.
said he has reached out to the
Radiation Therapy Oncology Group (RTOG) and the
National Surgical Adjuvant Breast and Bowel Project (NSABP), to
and NSABP are already talking about a merger. I have approached the chairs and
said we'd be the third, but they want to work out their own marriage before
they open the marriage," he said.
added his group is considering competing for one of the four new cooperative
group awards NCI plans to issue in FY14.
we are not chosen, [NCI] will have to face the political pressure of not
studying female gynecological cancers," he told BioCentury.
also is not moved by the IOM and NCI arguments that consolidating and
streamlining the groups will better enable them to engage in the translational
work necessitated by the advent of targeted therapies.
the groups have a plethora of really good science going on that's not part of a
protocol. You don't want to tamper with that," he said.
is not alone in his concerns that consolidation could result in fewer ideas
reaching the clinic.
hopes the number of ideas and studies goes up by decreasing the number of
groups, but it's not immediately clear how that will happen," said John Erban,
associate director for clinical science and clinical director of
Tufts Medical Center Cancer Center.
IOM report suggested the merger that formed the
Children's Oncology Group (COG) should serve as a template for
the adult groups.
Erban argued the pediatric groups had little choice but to merge because of the
scarcity of pediatric patients.
have 1,000 patients per year or 2,000 patients per year with particular
diseases and there simply can't be four cooperative groups enrolling different
trials. One breast cancer trial might require 3,000-5,000 patients, but many,
many more patients are eligible for those trials," he said.
Hussain, professor and associate director for clinical research at the
University of Michigan Comprehensive Cancer Center, also has
doubts that consolidation will result in more and better ideas. Hussain is
SWOG's prostate cancer committee, but said she was not speaking
on behalf of SWOG.
IOM report is legit, and they brought up very good points. But as an
investigator I am somewhat skeptical that the changes will actually improve the
process," Hussain said.
"may help in that you are bringing more brains together. But unless you bring
the resources and infrastructure, I don't see it. We participate in cooperative
groups as volunteers; we don't get paid to participate. And volunteers need
resources to accomplish big ideas," she said.
one of IOM's recommendations - that funding for the groups be increased - is
unlikely to happen any time soon. During a town hall meeting for NCI webcast on
Jan. 10, institute Director Harold Varmus said he did not expect any budget
increase for NIH, and that threats from Republican leadership in the House to
roll back funding to FY08 levels are "certainly real for 2012."
Varmus named fixing the cooperative groups as a priority, and said in the
absence of new funding, NCI would have to find the money elsewhere in its
"commitment base," the portion of the budget earmarked for things like salaries
and noncompeting grants.
details of how the groups will be funded have not been released. According to
its timeline, NCI will develop and issue new guidelines for a national clinical
trials network, plus the funding opportunity announcement, around July 2012.
from groups will be reviewed during 2013, with new awards to be issued in FY14.
four surviving adult groups and COG will undergo competitive review every five
years. All five groups will be reviewed in the same year "so that the Groups
can be directly compared and resources allocated appropriately, based on the
outcome," according to slides from Doroshow's presentation.
forward, Doroshow told BioCentury, the groups will be funded based on not only
their ability to develop trials, but also whether they work well with other
groups to bring forth novel ideas and accrue patients to studies that originate
at other groups.
if the stakeholders differ on how to accomplish the restructuring, they agree
it must be done to preserve patient access to clinical trials and effective
if the cooperative group mechanism does not work, for big, important trials,
people will go ex-U.S. That will decrease access to trials for U.S. patients
and will mean studies are not representative of the U.S. population for
approval," Desmond-Hellmann said.
and Hait both said that's already happening.
numbers tell the story: more and more registration trials are conducted outside
the U.S. Clinical research gives patients early access to the best drugs, and
having these trials exported reduces access for U.S. patients," Hait told
added: "If it takes too long, the groups will lose their relevance. I have a
sense of urgency about this. I think there's no excuse. We have the technology.
People have been talking about this for 15 years, and it hasn't made it better;
it has gotten worse."
College of Radiology Imaging Network (ACRIN), Philadelphia, Pa.
College of Surgeons Oncology Group (ACOSOG), Durham, N.C.
Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.
Ltd., Beijing, China
Idec Inc. (NASDAQ:BIIB), Weston, Mass.
and Leukemia Group B (CALGB), Chicago, Ill.
Oncology Group (COG), Arcadia, Calif.
Cooperative Oncology Group (ECOG), Philadelphia. Pa.
Inc., South San Francisco, Calif.
University, Washington, D.C.
plc (LSE:GSK; NYSE:GSK), London, U.K.
Oncology Group (GOG), Philadelphia, Pa.
of Medicine (IOM), Washington, D.C.
& Johnson (NYSE:JNJ), New Brunswick, N.J.
Cancer Institute (NCI), Bethesda, Md.
Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh,
Inc., South San Francisco, Calif.
Central Cancer Treatment Group (NCCTG), Rochester, Minn.
AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland
Health & Science University, Portland, Ore.
Therapy Oncology Group (RTOG), Philadelphia, Pa.
Ann Arbor, Mich.
Medical Center Cancer Center, Boston, Mass.
of California, San Francisco (UCSF), San Francisco, Calif.
of Michigan Comprehensive Cancer Center, Ann Arbor, Mich.