Clinical Trials Criteria
The PRECIS-2 Wheel of Trial Design
A visual example of how “explanatory” or “pragmatic” a trial is
FIGURE.
Eligibility
Primary analysis
Who is selected to
participate in the trial?
To what extent are
all data included?
5
Recruitment
How are participants
recruited into the trial?
4
Striking a Balance
3
Primary outcome
How relevant is it
to participants?
2
Setting
1
Where is the trial
being done?
Follow-up
Organisation
How closely are participants
followed-up?
What expertise and
resources are needed to
deliver the intervention?
Flexibility = adherence
What measures are in place to
make sure participants adh ere
to the intervention?
Flexibility: delivery
How should the intervention
be delivered?
Source: PRECIS-2. “About PRECIS-2.” Accessed September 26, 2016 from https://precis-2.org/Help/Documentation/Help.
“Patients on
clinical trials [are]
‘the Olympic
athletes of
patients’ because
they are the most
clinically fit of all
patients. ... They
do not reflect
the patients
walking through
the doors of our
clinics every day.”
—ABBY STATLER, MPH, MA
92
ASH Clinical News
In contrast, basket trials test the effect
of one drug on a single mutation that is
present in a variety of cancer types. The
phase II NCI-MATCH study, which looks
for actionable mutations in a patient’s
tumor and assigns treatment based on
the abnormality, for one, is designed with
the ability to add new treatments or drop
treatments over time.9
“explanatory” to “pragmatic” can visit
precis-2.org, a website designed as a
training resource and database of trials
that have been scored using PRECIS-2
(Pragmatic Explanatory Continuum
Indicator Summary-2). The tool was
developed in 2009, and modified in
2013, to “help trialists to think more
carefully about the impact their design
decisions would have on applicability.”7
PRECIS-2 is a nine-spoked wheel that
contains nine domains of trial design
decisions, including eligibility criteria
and recruitment (see FIGURE). The wheel
visually represents how explanatory
or pragmatic a trial is; trials that take
an explanatory approach produce
wheels nearer the hub and those with a
pragmatic approach are closer to the rim.
Umbrella and basket trials are two
types of trial designs that would score
“closer to the rim.” Umbrella trials are
designed to test the effect of a group of
different drugs on different mutations
in a single disease type. These trials are
designed to be more flexible and allow
for randomized comparisons and come
equipped with the ability to add or drop
biomarker subgroups. The BATTLE (Biomarker-integrated Approaches of Targeted
Therapy for Lung Cancer Elimination)
trial is an example of an adaptively randomized, umbrella study; it included 255
patients pretreated for lung cancer who
were adaptively randomized to erlotinib,
vandetanib, erlotinib plus bexarotene, or
sorafenib based on their relevant molecular biomarkers found during “real-time”
biopsies.8 Initial trial results showed that
there was an eight-week overall disease
control rate of 46 percent.
The road toward more pragmatic trials is
not without obstacles. A 2016 review of
pragmatic trials noted several challenges,
particularly in the area of trial recruitment.10 These challenges include:
• the difficulty in selecting participants
similar to those who would receive a
drug if it became usual care
• that volunteers for trials are often
healthier than the average person
• the possibility of financial incentives
to recruit to industry-sponsored
trials rather than academic trials
• the need for informed consent in
unselected participants
Also, in an attempt to increase the external validity of a trial, trialists run the risk
of over-correcting and jeopardizing the
trial’s internal validity.
To achieve a balance between internal
and external validity in trial design, Ms.
Statler recommended first tackling the
low-hanging fruit, like the requirement
that certain medical tests be performed
within an appropriate timeframe in order
for patients to meet trial eligibility criteria.
“Many studies in blood cancers require
bone marrow testing be performed within
14 days of the trial initiation and within
three or four weeks for certain patients,”
Ms. Statler said. “The disease is not likely
to change in that time, but these patients
will still not be eligible for the trial.”
Investigators should also look more
closely at the toxicity profiles of each
investigational agent and revise trial criteria based on the specific toxicity profile,
she added. “If a drug being investigated
does not have cardiac toxicities, it does
not make sense to exclude patients with
benign cardiac abnormalities at baseline.
If the drug is not going to exacerbate
the problem, there is no justification for
including those criteria.”
In addition to changing exclusion
criteria on a trial-by-trial basis, there also
are changes that could be made to the
regulatory process to address generalizability, Dr. Fowler said.
There will always be a need for tightly
controlled trials with a multitude of eligibility criteria at the beginning of an investigational agent’s trial life. As researchers
achieve positive results and move toward
a phase III study, they should also begin
to turn their attention toward addressing generalizability in parallel or soon
after, Dr. Fowler said, noting though that
those aspects typically are not budgeted or
planned for.
“Right now, the only incentive to
demonstrate efficacy is to get a drug
through regulatory mechanisms and into
clinical practice,” Dr. Fowler said. “There
is less incentive to look at the influence
of a drug in the usual patient population.
This is something that could be requested
or demanded in follow-up phases.” For
instance, a drug might be allowed to come
to market with the condition that investigators ensure that there are no adverse
effects or a decrease in efficacy when
indications for the drug are loosened, he
explained.
Dr. Singh agreed with this premise,
suggesting that one approach to solving
the challenge of balancing internal and
external validity might be to use a tool like
the Centers for Medicare and Medicaid
Service’s Coverage with Evidence Development,11 which would “provide approval
based on internally valid clinical trials,
and then assess generalizability with evidence generation in high-quality observational studies or subsequent trials.”
In the end, everyone ASH Clinical
News spoke with acknowledged that there
will never be an absolute wrong or an
absolute right way to balance internal and
external validity of clinical trials, while
bringing the most effective drugs to market quickly and safely.
“There will always be a push and
pull with internal and ex ternal validity,”
Dr. Hirsch said. “The challenge will be
finding the middle ground.” —By Leah
Lawrence ●
REFERENCES
1. Mitchel AP, Harrison MR, Walker MS, et al. Clinical trial participants
with metastatic renal cell carcinoma differ from patients treated in
real-world practice. J Oncol Pract. 2015;11:491-7.
2. Van Spall HGC, Toren A, Kiss A, et al. Eligibility criteria of randomized controlled trials published in high-impact general medical
journals. A systematic sampling review. JAMA. 2007;297:1233-40.
3. Statler A, Radivoyevitch T, Siebenaller C, et al. Eligibility criteria
are not associated with expected or observed adverse events in
randomized controlled trials (RCTs) of hematologic malignancies. Abstract #635. Presented at the 2015 ASH Annual Meeting,
December 7, 2015; Orlando, FL.
4. Bennette CS, Ramsey SD, McDermott CL, et al. Predicting low accrual
in the National Cancer Institute’s Cooperative Group Clinical Trials. J
Natl Cancer Inst. 2015;108:djv324.
5. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on
morbidity and mortality in patients with severe heart failure. N Engl
J Med. 1999;341:709-17.
6. Juurlink DN, Mamdani MM, Lee DS, et al. Hyperkalemia associated
with spironolactone therapy. Can Fam Physician. 2005;51:357-60.
7. PRECIS-2. “About PRECIS-2.” Accessed September 26, 2016 from
https://precis-2.org/Help/Documentation/Help.
8. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing
therapy for lung cancer. Cancer Discov. 2011;1:44-53.
9. National Cancer Institute. NCI-Molecular Analysis for Therapy Choice
(NCI-Match) Trial. Accessed September 21, 2016 from https://www.
cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/
nci-match.
10. Ford I, Norrie J. Pragmatic trials. N Engl J Med. 2016;375:454-63.
11. Centers for Medicare and Medicaid Services. Coverage with Evidence
Development. Accessed September 26, 2016 from https://
www.cms.gov/Medicare/Coverage/Coverage-with-EvidenceDevelopment/.
December 2016