March 2015
A CenterWatch Feature Article Reprint
Volume 22, Issue 03
Patient reported outcomes take center stage
FDA combining PROs,
clinical outcomes in
its approval decisions
By Ronald Rosenberg
Staff Writer
A
Incidence of subjective outcome assessments in clinical trials
Percent of total procedures per study
16.3%
11.8%
6.1%
growing number of clinical trials
now are going beyond conventional
randomized control measurements
to collect self-reported outcomes from patients—focusing on improving patients’ involvement by including their perspectives
throughout the drug development process.
But while interest in developing and applying patient-reported outcomes (PROs)
across the drug development and postmarket spectrum is growing—among
sponsors, clinicians, payers, regulators and
patients—progress has been slow.
The use of PRO measures in clinical trials
is growing—an analysis of sponsor-funded
interventional studies listed on CenterWatch’s Clinical Trials Listing Service
found between 2005 and 2007, only 6.1%
of total study procedures involved some
type of subjective outcome assessment.
That grew to 11.8% in the 2008 to 2010 time
frame and, most recently, between 2011
and 2013 increased to 16.3% of total study
procedures. PROs can capture a range of
information, from symptom changes and
2005–2007
2008–2010
2011–2013
Source: CenterWatch analysis of sponsor-funded interventional studies listed on its Clinical Trial Listing Service
level of functioning, to health-related qualify of life and treatment satisfaction and
adherence.Although their value is widely
recognized, PRO use often is inconsistent
and underutilized in understanding how
patients feel in relation to their diseases,
such as cancer, cardiovascular disease and
diabetes.
The FDA does not require sponsors to
consider PROs in clinical trials and, until recently, did not do much to encourage their use. However, signs point to that
sentiment changing in certain drug review
divisions.
“We understand that people with chronic diseases are experts in that disease, as far
as the symptoms and the impact on quality
of life, and what might be acceptable tradeoffs on risk and uncertainty,” Janet Woodcock, M.D., director of the FDA’s Center for
Drug Evaluation & Research (CDER), said
in her keynote address at the RPM Report’s
annual FDA/CMS Summit for Biopharmaceutical Executives last December.
The challenge for the FDA, she added, is incorporating that knowledge in a
way that accurately informs regulatory decisions.
“How can we meaningfully collect that
knowledge in a rigorous manner, given
there’s a spectrum of opinions and a spectrum of disease burden in any given disease?” she asked.
PRO measurements often are used to
evaluate products that treat chronic, disabling conditions, for which the goal of
treatment is focused on alleviating the
frequency, severity or duration of disease
symptoms. They generally are used as primary endpoints in clinical trials in indications such as migraines and irritable bowel
syndrome, in which specific symptoms play
“There has been a lot of progress made in the industry about
how to use adjudicators more efficiently. … With technology, it
has become more cost-effective and doable, compared to the
past when it was a very large investment.”
—Kathleen Mandziuk, scientific affairs director, late phase services at PRA Health Sciences
The CenterWatch Monthly (ISSN 1556-3367). Volume 22, Issue 03. © 2015 CenterWatch
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4%
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3%
4%
3% 3%
4%
16%
16%
18%
24%
Invasive procedures
X-rays and imaging
Heart activity assessments
Routine examinations
55%
50%
Questionnaires and subjective assessments
Lab tests and blood work
2000–2006
2007–2012
Source: Tufts CSDD 2013, N=2,671 phase II and III protocols <csdd.tufts.edu>
a major role in treatment. PROs also are important in the final product labeling manufacturers are allowed to use to promote their
products, and to clinicians seeking information to support their prescribing choices.
Now, trials for psychiatric and age-related
illnesses, among others, are including PROs
as part of the protocol design.
PROs v. clinical outcomes
But the increased reliance on PROs has
not come without concerns.
One is whether subjective reported outcomes (like “feeling better”) should trump
clinical outcomes. If a drug shows no hard
clinical evidence of being effective, yet patients report a positive effect, how should
the sponsor and the FDA treat this conflicting data?
“Most of the time, clinical outcomes will
be held as the ultimate outcome in a clinical
trial because they often provide more objective interpretation, increased reliability
and greater simplicity of interpretation,”
said Jason Cole, Ph.D., executive director,
global health economics & outcome research at PPD. “However, certain disease
conditions require one to consider subjective outcomes to be critically important.”
He said pain studies initially used PROs
as a primary outcome in a clinical trial
because attempts to obtain an objective
2 The CenterWatch Monthly | March 2015
measure of pain through a dolorimeter, a
spring-loaded instrument with a gauge for
measuring sensitivity to, or levels of, pain,
or through a galvanic skin response lacked
vali dity compared to simple pain scales.
Other diseases, usually in neurology, such
as depression and anxiety, often will have
co-primary or key secondary PROs.
Subjective outcomes sometimes are difficult to evaluate because they are more
qualitative in nature. So sponsors turn to
an outside “adjudicator” to assess the significance of PROs between cohorts of trial
participants—a situation that can increase
both the cost and time of a trial.
Several CROs say the number of adjudication projects has declined in recent years
because of advances in technology, while
others say the biggest change has been
streamlining the process to enhance their
efficiency and effectiveness. Adjudication
typically is required for a relatively small
number of clinical outcomes assessments
to address regulatory questions.
“We’ve had studies in which adjudication is involved, particularly where you
are looking at some hard endpoints, such
as imaging, and where an outside view on
some very particular critical results requires a judgment and determination,”
said Kathleen Mandziuk, scientific affairs
director, late phase services at PRA Health
Sciences.
centerwatch.com
IndustryNews
“There has been a lot of progress made in
the industry about how to use adjudicators
more efficiently,” she said. “We use an electronic adjudication methodology that allows
us to upload source documents and provide
immediate viewing and processing by external reviewers. It’s an important component
for certain studies, particularly if there is a
concern about over- and under-reporting
around safety events or for a diagnosis. So
with technology, it has become more costeffective and doable, compared to the past
when it was a very large investment.”
Increased patient centricity
In giving trial participants a greater
voice through PROs, sponsors and CROs
also are moving toward greater patient centricity. Some industry observers predict increase use of hand-held technology, in the
form of smart phones and other devices,
to assist study volunteers. However, the increased use of hand-held technology, currently used in many trials to monitor blood
pressure and other concrete measures, does
not lead necessarily to an increase in their
use to measure PROs.
“Patient-provided devices will need
more evaluation before they are used more
for the collection of PROs in clinical trials,
even though post-approval studies already
have seen an increase in such activity,” said
Cole of PPD. “It’s probably safe to say smart
phones and other devices will continue to
grow in use to ensure patients remain engaged in clinical trials.”
Keeping trial participants involved also is
the hallmark of the publication and promotion of the FDA’s PRO guidance at the end
of 2009. In 2011, the FDA took the next step,
seeking multiple ways to give the patient
a clear voice in clinical research by ensuring all measurements and outcomes reflect
what is happening with the patient through
instruments or tools, along with PROs.
“Increasingly, we are seeing patients in
clinical trials saying, ‘I demand to know
3 The CenterWatch Monthly | March 2015
Incidence of adjudicated endpoints
Percent of Total
69%
41%
FDA approvals
EMA approvals
Source: Krumholz-Bahner et al. 2015; N=35 NMEs recently approved by FDA; N=88 NMEs recently approved by EMA
what is going on’ and they want to be given
a greater voice, which can take many forms
of greater involvement through technology,” said Jean Paty, Ph.D., senior director and practice lead-endpoint strategy for
consulting at Quintiles. “Giving the patients the opportunity to have their voice,
not only in trials, but also as contributing
to science and to a drug product’s final label, has been a long, continuing process.”
Part of that process is determining
whether the increase in the number of PROs
has increased the burden on investigative
sites. Whether using paper PROs that sites
have to ensure are completed and then enter
the data, or electronic data capture (ePRO),
sites take on an added responsibility.
Some sites have their own help desks to
assist patients with IT problems. Generally, larger sites can handle adding PROs
more easily, while smaller sites, especially
in more remote locations, can find it more
challenging, said Cole.
Mandziuk said data collected directly
from the patient that does not go through
the sites can provide stronger information.
One example, she said, is that patients can
be hesitant to report outcomes if they have
been asked to take a medication a certain
way and have not done so.
“Are they going to be up front about
that information if they have to go back to
their physician and tell him, versus telling
a third party independent of that physician, that they didn’t follow the rules?” said
Mandziuk. “Collecting that data through
specific data streams provides, in some cases, better quality. Patients will contact the
independent group and not necessarily go
back to their physicians for technical issues
and concerns.”
Looking ahead
While using PROs is becoming critical
in many clinical trials to prove safety and
effectiveness to gain FDA approval, the
next step for biopharmaceutical companies
and payers will be to combine PROs with
other observational studies to create realworld evidence (RWE).
RWE is becoming essential for sound
medical coverage, payment and reimbursement decisions, according to the
International Society for Pharmaeconomics Outcomes Research Real-World Data
Task Force.
RWE can be used with randomized
clinical trials to design more efficient trials
and understand a drug’s benefit-risk profile, as well as to gain understanding of the
market for launch planning, according to
the task force.
“Real-world evidence shows how a drug
is accepted from patients who have experience using it,” said Yin Ho, founder and
CEO of Context Matters, a provider of
health economics outcomes research data.
“It reveals how a drug is utilized in some
part of the world in policy or regulatory
decisions. It’s a highly credible source of information.” centerwatch.com