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LAURA E. STRONG
HOW ARE PROS USED IN ONCOLOGY DRUG
DEVELOPMENT?
PROs can be used as endpoints in oncology clinical trials, resulting
in symptom improvements that may be listed in label
claims of drugs approved by the FDA.
Endpoints used for FDA approval of new cancer drugs from
January 1990 to November 2002 were reviewed. 21 Changes in
symptoms related to tumors were responsible for 4 of 57 approvals
including the use of mitoxantrone in hormonerefractory
prostate cancer (HRPC), approved solely for pain
relief. From January 2002 to September 2006, 6 of 70 new or
revised oncology drug labels included PRO assessments. 22
These drugs included gemcitabine, imatinib, abarelix, leuprolide
acetate, interferon alfa-2b, and palifermin.
While noting challenges (e.g., missing data), the FDA’s
Guidance to Industry in 2007, “Clinical Trial Endpoints for
the Approval of Cancer Drugs and Biologics,” included
symptom endpoints as suffıcient evidence for regular approval.
23 Based on draft guidance in 2006, the FDA published
a guidance document in 2009 called “Patient-Reported Outcome
Measures: Use in Medical Product Development to
Support Labeling Claims.” 12 Although an oncology-focused
review is not available, an overview of the PROs in labels
from 2006 to 2010 reveals that the Biologic Oncology Products
and Drug Oncology Products divisions at the FDA did
not grant any PRO labels claims. 24
Separately, a review of the drug approval packages for New
Molecular Entities and Biologics License Applications for
drugs approved from January 2006 through December 2010
was performed to evaluate the use of PROs. 25 A total of 116
approvals across all therapeutic areas were evaluated. Although
there are alternative reasons to include PROs, this review
assumed that all PROs included in a drug approval
package were intended for approval. Among 52 drugs for
which PROs were included in pivotal studies, 28 had one or
more PRO claim approved. Eight cancer drugs were “denied”
PRO claims in this time period. For comparison, 18 oncology
applications were submitted over the same time period. 24
Across all sectors, but specifıcally in oncology, the major reasons
that PROs did not support claims included “fıt for purpose”
and study design/data quality/interpretation. As
noted, providing detailed evaluations of the PROs and their
use would allow sponsors to better meet FDA standards in
the future. 25
Prostate cancer provides a strong example of the use of tumor
symptoms as endpoints in oncology drug development.
Pain and skeletal-related events are among the major diseaserelated
symptoms of HRPC. The supplemental approval of
mitoxantrone in 1996 was for pain relief in HRPC. 21 The approval
of docetaxel in 2004 was based on survival benefıt as
the primary endpoint. Two clinical trials comparing mitoxantrone
and docetaxel with secondary endpoints of PROs
were inconclusive as one study was positive and the other
negative. 26,27 A review of PROs and chemotherapy in clinical
trials of HRPC indicates that the PROMs were generally validated,
even if they were often used as a secondary endpoint.
26 Although bisphosphonates have been approved for
use in HRPC to reduce skeletal-related events, the corresponding
improvement in pain did not lead to an improvement
in function or quality of life, illustrating the challenges
associated with these and other new agents. 21,27
In a recent review of PROs in randomized clinical trials
(RCTs) of prostate cancer from January 2004 to March 2012,
the authors estimate that approximately 20% of the RCTs
provided suffıcient data to change clinical practice. 28 The authors
compared their work to a similar review covering RCTs
from 1980 to 2001 and indicate that the use of PROs in RCTs
has improved. One area of improvement was that the number
of trials with documentation of missing data increased
from 48% to 72%. Unfortunately, only 18% of the newer trials
addressed statistical treatment of the missing data. This issue
reflects the concerns expressed by the FDA in the examples
given above. Adding to the discussion, an organization called
CONSORT (Consolidated Standards of Reporting Trials)
has recently published specifıc recommendations to improve
the reporting of RCTs that include PROs. 29
The most recent generation of FDA-approved drugs for
prostate cancer includes abiraterone, cabizataxel, enzalutamide,
radium Ra 223 dichloride, and sipuleucel-T. Clinical
registration trials for each of these products included PROs.
Notably, the products were approved from 2010 to 2013, following
release of the draft and fınal FDA guidance on PROs.
In the United States, the FDA granted pain symptom claims
based on PROs to two of the fıve drugs, enzalutamide and
abiraterone. 30 A review has collected background information
for the rejection of the remaining claims by the FDA,
showing that the reasons largely overlap with those for rejections
from 2006 to 2010 (e.g., validity of the instrument or
missing data). 30
ARE THERE OTHER USES FOR PROS?
In addition to providing direct benefıt to patients, PROs can
be used for a variety of other purposes. PROs can be captured
to explore disease progression and could assist in the development
of improved diagnostic tools or potentially even new
interventions, including new targets for drug development.
Large academic medical centers fıt into this stakeholder category
because they have electronic health records and often
have access to existing PROMs. However, another intriguing
example is Open Research Exchange, which is a collaborative
project developed and run by the online patient community
network PatientsLikeMe. 31,32 Their goal is to attract researchers
to Open Research Exchange to develop and test
health outcome measures within the patient communities of
PatientsLikeMe. Although the company is for profıt, the
Open Research Exchange advisors include many of the leading
academics involved in PROs, including Dr. Ethan Basch
from the Lineberger Comprehensive Cancer Center at the
University of North Carolina.
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2015 ASCO EDUCATIONAL BOOK | asco.org/edbook