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Capturing and Evaluating
Patient Reported Outcomes (PROs)

Last update: 02/23/2016

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In the News | Advocate Perspectives | Studies recruiting patients | Research News | Instruments and Guidance
“Health is a state of complete physical, mental, and social well-being—
not merely the absence of disease, or infirmity.” —-World Health Organization, 1948

 

The terms Patient Reported Outcomes (PRO) and Quality of Life (QOL) are sometimes used interchangeably and this seems to be a source of confusion and is perhaps contributing to the slow adoption of these tools.  

Some important symptoms of the disease or side effects of a therapy can only be known and reported by the patient - such as pain, fatigue and depression.  These are sometimes called Patient Reported Outcomes (PROs).  Instruments to measure PROs are needed to judge the clinical impact of treatments but also to manage and care for the whole patient.  

Such as:


 

Sloan, Jeff, MD: PowerPoint presentation

What is quality of life (QOL)?

"Quality of life (QOL) is a popular term that conveys an overall sense of well-being, including aspects of happiness and satisfaction with life as a whole. It is broad and subjective rather than specific and objective. What makes it so challenging to measure is that, although the term “quality of life” has meaning for nearly everyone and every academic discipline, what it actually means is somewhat different for each individual and group. How do you reach accord about a measure for quality of life? Perhaps the strongest area of a consensus is that quality of life is extraordinarily broad and conceptually complex, yet measures are most meaningful when they measure key concepts in a logical way and are as precise as possible."   

* CDC: Measuring Healthy Days
Population Assessment of Health-Related Quality of Life http://www.cdc.gov/hrqol/pdfs/mhd.pdf

Patient Reported Outcomes (PROs).  

The FDA guidance document below describes the importance of such instruments as a basis for making medical claims, and the challenges of designing instruments that are reliable for that purpose.  Effective QOL instruments would be standardized, easy to administer and use, and reliable as a way to assess disease symptoms and treatment side effects that can be identified in no other way.
 


An Advocate's Perspective on PRO and QOL measures ... 
for Investigators and Drug Sponsors:

The terms PRO and QOL are sometimes used interchangeably and this seems to be a source of confusion and is perhaps contributing to the slow adoption of these tools.   There are two potential uses for Patient-reported Outcomes (PROs) in clinical trials and in regular practice. 

1) The first is to monitor the patients for significant changes in their overall status that would not otherwise be captured. 
(For example:  In week 2 on treatment A, a sharp increases in pain, or fatigue or anxiety was reported.  Should we stop therapy?   Should we change treatment, adjust the dose, or give medications to help manage the side effect? )

2) The second is to measure patient reported outcomes as endpoints in a clinical trial -- to help compare one treatment against another.   (For example:  treatment A and B were equivalent in terms of response rate and duration; however the participants who received Treatment B experienced much more pain, or fatigue, or depression).      

PROs might be thought of as way to obtain information that is specific to a common symptom of the disease or an anticipated side effect of the study drug.  QOL instruments will also obtain the patient's experience of pain or fatigue, but can provide valuable information about the whole patient (global changes) - such as changes to the patient's sense of well-being.  Since such reports are inherently subjective it will be important to obtain baseline measures so that each patient becomes the control.  For example, if a small number of patients develop neuropathy after treatment when this pain was not reported before, this could be a important signal for an uncommon side effect that would not have been otherwise detected.

The use of standardized QOL instruments in all trials would:

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Better monitor and improve patient safety
(e.g., test for need to reduce dose when indicators drop suddenly)

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Proactively identify patients in trouble
(e.g., are in danger of dropping out for safety / financial / social / physical / emotional reasons)

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If standardized, will help to compare populations across studies in a another way -
noting the low QOL scores are associated with poorer survival.*
(e.g., QOL scores were comparable in the two study groups)  * http://bit.ly/1rCQqSj

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And to help to Inform about outcome that are important to patients, which are measured poorly in other ways
(e.g., depression, pain, fatigue).    

The significance of the patient experience with treatment may increase as the duration of therapy increases - particularly if the intervention does not provide a survival advantage (all treatment roads lead to a similar destination). 

Further, when there is no standard best practice, the importance of the impact of treatment on quality of life increases. On this, David
writes:  "It is possible that a larger and larger frequency of patients will successfully be rescued by the newer techniques over the next ten years. More and more people will die of something else besides lymphoma or the iatrogenic (treatment-related) results of lymphoma treatment."

That we are asking the patient about their experience shows that we care about them and are committed to following them (the whole patient) carefully to identify needs and changes in their well being.

QOL endpoints may be particularly important to capture when the duration of treatment is long (e.g., many months or indefinitely until relapse or for extended periods of time) ... as a way to understand the impact of the treatment on the patient's life (including financial toxicities).

The subjective nature of what patients will report can be a challenge. Is the report of pain real or attention seeking? What is the influence of the patient's expectations - or a recent favorable test result showing the cancer retreating? Here the baseline PRO can help to account for such factors by including questions about his or her expectations and what the patient has learned about the response to treatment from formal tests or observations – and by accounting for other common stressor in life, such as financial (e.g., can’t pay the rent) and social (e.g., spouse filing for divorce).

In the future we might apply an easy-to-use standardized PRO/QOL tool as we would any laboratory test as an important way to understand and monitor the patient – one that cannot be done in any other way. Patients want to be asked so long as the instrument is concise and easy to complete.  The affordability of administering surveys can be addressed by developing standardized and concise PRO instruments (Sloan, Mayo) and automated scoring systems.
 


PROs: Opportunities and Challenges

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Software can streamline the reporting of symptoms (e.g., making use of conditional branching) so that the survey does not have to inquire of the patient about each of the 70 or so possible side effects that rely on patient reporting - and the process does not require medical personnel to capture patient reported side effects.
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How to streamline the process of reporting so that it's not a burden to the participants in a study and it does not add substantially to the cost?
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Relatively minor side reported earlier may predict more serious side effect that present later.
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Will the reporting instrument need to be adapted for different kinds of studies, study drugs, and study designs?
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How to account for the placebo effect - particularly in single arm studies?


PROs: Might the placebo effect be a confounder?

Study design will have to take into account (control for) the placebo effect ... as the symptoms that can be reported only by the patient (fatigue, nausea, and pain) can be influenced by our belief and expectations about the intervention.

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NEJM Research reveals placebo effects to be genuine biopsychosocial phenomena. How can this be used to benefit patients? http://nej.md/1f11kPa  

 Snip:

First, though placebos may provide relief, they rarely cure. Although research has revealed objective neurobiologic pathways and correlates of placebo responses, the evidence to date suggests that the therapeutic benefits associated with placebo effects do not alter the pathophysiology of diseases beyond their symptomatic manifestations; they primarily address subjective and self-appraised symptoms. For example, there is no evidence that placebos can shrink tumors; however, experiments demonstrate that common symptoms of cancer and side effects of cancer treatment (e.g., fatigue, nausea, hot flashes, and pain) are responsive to placebo treatments. … This conclusion tracks evidence related to many conditions, such as musculoskeletal, gastrointestinal, and urogenital disorders.


PRO Studies recruiting patients:

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Patient-reported outcomes (PRO) in| lymphoma studies - ClinicalTrials.gov http://1.usa.gov/1QZgCEX
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Patient-reported outcomes (PRO) in cancer - ClinicalTrials.gov http://1.usa.gov/1dsBRfU
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Standardized Geriatric Assessment or Usual Care in Improving Communication and Quality of Life in Older Patients
http://1.usa.gov/OYF6iR 
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Search of: QOL | Studies With Results - List Results - ClinicalTrials.gov http://1.usa.gov/1Tl9OiI

 


Resources and Research News

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JCO 2016:
Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment:
A Randomized Controlled Trial http://bit.ly/20MbHw7

Important finding!
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FACTIT.org PRO Questionnaires http://bit.ly/20IYCng
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NCI - an excellent overview of this initiative.
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events
brochure PRO-CTCAE.pdf
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Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) http://1.usa.gov/1xSvHv0
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Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf
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JCO, 2012: Recommendations for Incorporating Patient-Reported Outcomes Into
Clinical Comparative Effectiveness Research in Adult Oncology http://bit.ly/RXoy7j
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Quality of life data as prognostic indicators of survival in cancer patients: overview of literature - 1982 to 2008 http://1.usa.gov/1kXovH2
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PPM: Placebos in Pain Management http://bit.ly/1aysa80

A reason that studies recording patient reported outcomes (PROs) for new agents may need to have a placebo control
Sloan et al:
Prognostic significance of baseline quality QOL for OS among 3,704 patients --
 ASCO Meeting Abstracts http://bit.ly/1rCQqSj

Baseline QOL (quality of life) is a strong and independent prognostic factor for OS over and above PS (performance status) in a wide variety of oncology patient populations and should thus be considered for routine inclusion as a stratification factor for all future randomized oncology treatment trials.
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JCO, 2012: Relationship Between Deficits in Overall Quality of Life and Non–Small-Cell Lung Cancer Survival http://1.usa.gov/1povHNK

Overall QOL measured by a simple single item at the time of lung cancer diagnosis is a significant and independent prognostic factor for survival in patients with lung cancer.
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Guidance for Industry -- Patient-Reported Outcome Measures:
Use in Medical Product Development to Support Labeling Claims

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf 

“A PRO is any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else. The outcome can be measured in absolute terms (e.g., severity of a symptom, sign, or state of a disease) or as a change from a previous measure. In clinical trials, a PRO instrument can be used to measure the effect of a medical intervention on one or more concepts (i.e., the thing being measured, such as a symptom or group of symptoms, effects on a particular function or group of functions, or a group of symptoms or functions shown to measure the severity of a health condition).

Generally, findings measured by a well-defined and reliable PRO instrument in appropriately designed investigations can be used to support a claim in medical product labeling if the claim is consistent with the instrument’s documented measurement capability.

The amount and kind of evidence that should be provided to the FDA is the same as for any other labeling claim based on other data. Use of a PRO instrument is advised when measuring a concept best known by the patient or best measured from the patient perspective. A PRO instrument, like physician-based instruments, should be shown to measure the concept it is intended to measure, and the FDA will review the evidence that a particular PRO instrument measures the concept claimed. The concepts measured by PRO instruments that are most often used in support of labeling claims refer to a patient’s symptoms, signs, or an aspect of functioning directly related to disease status. PRO measures often represent the effect of disease (e.g., heart failure or asthma) on health and functioning from the patient perspective.

Claims generally appear in either the Indications and Usage or Clinical Studies section of labeling, but can appear in any section. Regardless of the labeling section, PRO instrument evaluation principles described here apply.”

Comment: So this guidance is specific to studies designed to make a medical claim based on outcomes reported by the patient – a prospectively defined primary endpoint.

However, PROs can also be tools to help physicians and study doctors to understand their patients -- monitoring for changes in QOL, functioning, treatment-related side effects (pain, fatigue), disease symptoms, etc.. Identifying patients who have need for social services, medication for anxiety … or perhaps when to evaluate for relapse.  KarlS
 
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Quality of life data as prognostic indicators of survival in cancer patients: overview of literature - 1982 to 2008 http://1.usa.gov/1kXovH2
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An Evaluation of Age-related Differences in Quality of Life Preferences in Patients with Non-Hodgkin's Lymphoma. Leuk Lymphoma. 2004 Dec;45(12):2471-6  PMID: 15621762 

See also Lymphoma in elderly patients
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Quality of life among long-term non-Hodgkin lymphoma survivors:
a population-based study. Cancer. 2007 Mar 1  PMID: 17330853 

From 5 to 15 years after diagnosis, the general health perceptions and vitality levels of non-Hodgkin lymphoma survivors remained significantly lower than those of their peers in the of general population.

In addition, survivors faced practical problems with work and finances that deserve additional attention during the period of rehabilitation.
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Study Finds Overall Health and Quality of Life Intact 10 Years After Stem-Cell Transplantation  prnewswire.com 
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Preliminary evidence of relationship between genetic markers and oncology patient quality of life (QOL)  ASCO Highlights 

"Is there a relationship between the state of cancer patients' genetic structure and their quality of life? Genetic variants have been associated with patient toxicity or clinical outcome. There has been little work done exploring the relationship between genetic variants and patient QOL."
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First-line treatment with brief-duration chemotherapy plus rituximab in elderly patients with intermediate-grade non-Hodgkin's lymphoma: phase II trial. Clin Lymphoma. 2003 Jun; 4(1): 36-42  PMID: 12837153
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Instruments and Guidance

Objectively measuring symptoms can be challenging in clinical research. But tools are available that can help.
 

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Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) http://1.usa.gov/1xSvHv0
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CDC - HRQOL-14 (in public domain)
Healthy Days Measure - HRQOL http://1.usa.gov/1eUCJKi
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Oncologypractice.com:
Patient-Reported Outcomes in Chemotherapy-Induced Peripheral Neuropathy: A Review
http://www.oncologypractice.com/jso/journal/articles/0806e15.pdf 
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Developing Pediatric Patient-Reported Outcome (PRO) Instruments for Clinical Trials to Support
Medical Product Labeling: Challenges and Good Practices
 http://www.fda.gov/downloads/AdvisoryCommittees .pdf
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Guidance for Industry:
Patient-Reported Outcome Measures: Use in Medical Product Development
to Support Labeling Claims  fda.gov
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Jeff A. Sloan, Ph.D. a leader in QOL research:
http://mayoresearch.mayo.edu/staff/sloan_ja.cfm
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Commentary: The FDA guidance for industry on PROs:
the point of view of a pharmaceutical company http://www.hqlo.com/content/4/1/85
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2002 Sep;16(9 Suppl 10):133-9. Review 
Assessing quality of life in research and clinical practice. Oncology (Huntingt).   PMID: 12380963 | Abstracts
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A COMPARISON OF THE EMEA AND FDA DRAFT GUIDELINES IN CONGESTIVE
HEART FAILURE (CHF) WITH PARTICULAR REFERENCE TO QUALITY OF LIFE OUTCOMES
http://www.eriqa-project.com

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