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Advocacy  / Research Tools >  Research Advocacy Resources

Last update: 11/07/2017

Checklists for Review of Concepts | Background and references | Low versus High Risk FL
Endpoints - PROs  | Ethical Principles of Research (Belmont report)

Lymphoma Research: an advocate's perspectives  | Concept Review Tips/worksheet

 

It's a learning journey  

Clinical research advocates - helping patients to think more like scientists
and scientist to think more like patients, who are the primary stakeholders in clinical research

Research advocates engage scientists, review research priorities, concepts, protocols and informed consent documents.  As representatives of the primary stakeholders in clinical research, our role is to provide the patient perspective - such as how the community is likely to perceive the research, the burden of research-related tests, the feasibility of accrual, and the importance of the study questions to patients. 

We are people from all walks of life who wish to engage and help scientists to carry out research in order to make progress against the disease that afflicts us, or a loved one, and our community.  We are experts about the experience of treatments and what it is like to live with the disease.   While the overwhelming majority of researchers are themselves sincere advocates for patients, we can provide unique perspectives and ideas that can enhance the quality of the study design and the feasibility for timely accrual.  Advocate involvement and vetting of clinical research also helps to establish public trust in research, which enhances funding. 

Because many aspects of clinical research are technical, it's important for research advocates to "know what we don't know," to be good students of clinical science, and to seek mentors to consult when we are uncertain about a research issue.  In many cases, the QUESTIONS we ask ... will be much more effective at influencing outcomes at scientific meetings than declaring a firmly-held opinion.   

To achieve standing among experts in the field - to be heard and to influence the outcomes of discussions - advocates should be good students of the following:

  1. The natural history of the disease - its expected clinical course and who it tends to effect

  2. The standard of care or best practice for the disease - the context against which study protocols emerge and the need for improved therapies are assessed.

  3. Scientific methods (clinical study design) - what types of studies are needed to provide reliable (reproducible) information to advance clinical practice or gain understanding of the biology of the disease in order to guide clinical science.

  4. The history of drug development and regulatory review is very helpful - to provide an understanding of endpoints chosen to measure outcomes in the tests of clinical protocols.

  5. Ethical principles of research, such as respect for persons

  6. The informed consent process and documents for the purpose of helping the patient who is considering a trial to make an informed choice.

Research advocate represent the patient community. Therefore it's important for advocates to engage our communities to understand their needs, concerns, and perceptions.  We are liaisons - who can help explain the science and study rationales to the community, and explain the perceptions and concerns of the patient to the scientists.

It's important for advocates and scientists alike to keep an OPEN MIND.

We should be cautious about vigorously promoting a particular approach to research (having an agenda) based on our own circumstances and experiences, unless it is one that is widely shared by the community or supported in the medical literature.   Consulting our mentors prior to making science or study design proposals is essential to do before making such recommendations.

Checklist for Advocates
when Reviewing Study Concepts and Protocols

* Also see PDF checklist that is more complete as of this writing:
 Form-worksheet-for-study-concept-evaluations.pdf

Building on recommendations of seasoned research advocates - participants in the cooperative groups and at AACR / ASCO events.

Scientific rationale for choosing the study drug or protocol - is it strong?

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Review literature then inquire if needed:

Why made you choose the particular drug you’re investigating?

If there were no constraints, which other drugs (experimental or approved) or combinations might you prefer to study?

How might you overcome the constraints?

Study questions - relevance to patient needs and goals?

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What is the therapeutic goal of therapy that can reasonably be expected?

What will be the participants expectation after reading the consent document?

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Is the study question important to patients?  Explain?

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What is the expected impact of the treatment protocol and procedures on quality of life?

Is the treatment period longer than regular care?  If so, will you measure for impacts on quality of life?

Randomized trials - common issues:

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Is there an effective therapy to compare the study protocol to?

If not, could a larger single-arm study answer the question reliably?

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Is there genuine uncertainty about relative risks and benefits for both arms of a randomized trial?

Is there a widely held perception that one or the other approach is better, even if not proven definitively?

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Do the compared protocols have similar, or very different, toxicity profiles and risks?

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Can a crossover option be provided for participants who have toxicities or fail to benefit from the study or control protocol - based on interim scans or observation? 

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Will Quality of life measures be taken to compare the clinical impacts of the compared protocols?

Patient-reported outcomes and measures will be important for patients - especially when other efficacy and toxicity endpoints are found to be similar in a controlled study.

Justice (Belmont principle) - patient selection / eligibility:

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Do the eligibility criteria exclude large segments of the patient community?

Can the eligibility be modified to make sure the findings are generalizable to the patients in need?

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How rapidly do you anticipate accruing patients?

Would you prefer to accrue more rapidly? If so, what might you do?

What would be lost or gained by changing the eligibility criteria?

What could be gained by making your trial more inclusive (e.g., including patients with different tumor types, at different stages, and/or with different treatment histories)

or less inclusive (e.g., restricting it to patients who have a particular bio-marker and/or with fewer previous treatments)?

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Relevance of study question when the study is complete and the data is mature?

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When do you anticipate completing your trial?
Given other ongoing work in your field, how likely is the result to be relevant then?

Respect for persons (Belmont principle): Feasibility - is study protocol attractive to patients?

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What other trials or regular treatments might be more attractive for eligible patients?

Does this suggest any ways you might modify your trial?

Will you list these alternatives specifically in the informed consent?

Do no harm - (beneficence)

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What are the procedures (biopsies, blood sticks, imaging) needed for the study that may impact accrual in the study? 

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How do the procedures needed for the study compare (in number and by risk) to what the patient would receive with regular care?

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If a patient does not do well while in your study (e.g., has unacceptable toxicity, has disease progression),
what will you offer him/her (e.g., crossover to different treatment arm)?

If a patient is doing well at the conclusion of your study, what will you offer him/her (e.g., continued access to drug)?

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If you find that you are not accruing at the rate you planned, what actions will you take?

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How likely are you to recruit minority and other medically underserved patients?
What can you do to increase your recruitment of these patients?

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Brainstorm all of the likely and less likely outcomes of your study.
For each, list the type of follow-up (e.g., next study) you would do.

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Are there any outcomes that will leave you unsure what to do next? If so, is there a way to change your design to reduce or eliminate the likelihood of that potential outcome?

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Brainstorm all of the things you can think of that might go “wrong.” For each, list what you will do if the problem occurs? Are there ways to design the study to reduce or eliminate the risk of these problems?
 

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Draw a timeline (Day Calendar) of interventions your patient will receive?
Is the burden reasonable to expect from a patient as sick as the likely patient in your study? Are there ways to minimize the number of visits to the clinic (e.g., combine visits for diagnostic tests and treatments)?

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Are there data that would be relatively easy (and non-onerous to patients) to collect while you are conducting this study that might be useful in the future (e.g., biopsies, blood, QOL measures)? Are there collaborators that you could include to make use of such data?
 


Informed Consent -- Checklist

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Essential elements of Informed Consent  fda.gov

[Code of Federal Regulations] 

PROTECTION OF HUMAN SUBJECTS

Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject:

(1) A statement that study involves research,

- an explanation of the purposes of the research and the expected duration of the subject's participation,
- a description of the procedures to be followed,
- and identification of any procedures which are experimental.

(2)
A description of any reasonably foreseeable risks or discomforts to the subject.

(3)
A description of any benefits to the subject or to others which may reasonably be expected from the research.

(4)
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.

(5)
A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.

(6)
For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.

(7)
An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.

(8) A statement that participation is voluntary,
that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

See for additional information: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=50.25

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Illustrations should be provided to present complex information

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Day calendar showing what they patients can expect

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Labeled as regular vs. investigational procedure

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Labeled as therapeutic vs. non-therapeutic 

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Labeled as guiding care of participant vs. gaining knowledge for future patients

Background and Resources

Sources of Bias and Science-based Methods to Minimize

bullet Abbreviations Oncology-Research-Glossary-10-30-15-NCI.pdf
 
bullet PAL items
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"Giving" Tissue and Blood for Research - an advocate's perspective Giving-blood-and-tissue-2014.pdf
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Questions that can only be answered by clinical trials PDF
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The Problems with Testimonials by PAL
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Evaluating medical claims and data by PAL
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End Points and United States Food and Drug Administration
Approval of Oncology Drugs By John R. Johnson, Grant Williams, and Richard Pazdur - FDA

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Design of Phase I Combination Trials:
Recommendations of the Clinical Trial Design Task Force of the NCI Steering C. http://bit.ly/1Dz0rDi

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Dose Escalation Methods in Phase I Cancer Clinical Trials
Christophe Le Tourneau J. Jack Lee Lillian L. Siu
JNCI: Journal of the National Cancer Institute, Volume 101, Issue 10, 20 May 2009, Pages 708–720 http://bit.ly/2j6lL4r 
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Eliminating Bias in Randomized Controlled Trials:
Importance of Allocation Concealment and Masking

http://www.stfm.org/fmhub/fm2007/February/Anthony132.pdf 

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Bias in randomized controlled trials blackwellpublishing.pdf 

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NCTN 2014 Working Group Report on Cooperative Group Trials
This report describes strengths and weaknesses of NCTN studies by disease type (portfolio)
http://deainfo.nci.nih.gov/advisory/ctac/0714/Sledge.pdf

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NEJM - Perspective: Expediting Drug Development —
The FDA's New “Breakthrough Therapy” Designation http://bit.ly/1nX1mdm

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FDA Patient Representative Workshop - videos available for each session http://bit.ly/YXBAuS 
 

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What is advocacy? wpas-rights.org

Identifying Your Biases

All people develop attitudes, preferences and biases.  However, in order to be an effective advocate, you must be able to recognize your own attitudes, preferences, and biases.  If you don't your attitudes are likely to interfere with your judgment. You could take positions which reflect your biases, rather than the choices of the people for whom you advocate.  You may interpret the actions of others cynically, or naively, and thereby lose your ability to work effectively for the interests of others.

Informed Consent and Concept Review Materials

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CTEP forms for advocates and investigators  CTEP

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Tables of Possible Side Effects for Commonly-Used Oncology Drugs

Note: The Tables of Possible Side Effects provided below are designed so they may be cut-and-pasted into the “What possible risks can I expect from taking part in this study?

 https://ctep.cancer.gov/protocolDevelopment/sideeffects/drugs.htm

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Informed Consent Template for Adult Cancer Trials  Cancer.gov

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Simplification of Informed Consent Documents Cancer.gov

Purpose of the Study - The purpose of this research study is to find out whether adding the drug XYZ to a commonly-used chemotherapy is better at preventing your cancer from coming back than the commonly-used chemotherapy by itself.

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Consent, at-a-Glance, compiled by PAL  discussion.pdf

Advocacy Programs

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Advocacy Programs (CARRA, FDA Patient consultants programs, NCI Director's Liaison, IRB, etc.)

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FDA Advisory Committee  - Patient Representative program  fdaadvisorycommittee.com 

Comment on Proposed Regulations and Submit Petitions   www.fda.gov/
any citizen may submit a petition on any matter of concern under the jurisdiction of FDA
 

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Clinical Trial Design and Participation  Consulting with Patients, the FDA, Drug Sponsors, the NCI, and community physicians. Establishing credibility through hard work and financial independence.

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Overcoming obstacles to participation in clinical trials  Patient Perspective

Biospecimen issues and resources

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Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK): Explanation and Elaboration http://1.usa.gov/1wb5zim

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JCO, 2012: Ethics of Mandatory Research Biopsy for Correlative End Points Within Clinical Trials in Oncology http://bit.ly/1s0u1vx 
 

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2006 by American Society of Clinical Oncology
Are We Taking Without Giving in Return? Ethics of Research-Related [Serial] Biopsies & Benefits of Trial Participation http://bit.ly/1A1TdYp 

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Issues in collecting, processing and storing human tissues and associated information to support biomedical research http://1.usa.gov/13XxrJr

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NCI Biospecimen Best Practice - Consent, ownership, standards http://biospecimens.cancer.gov/bestpractices/2011-NCIBestPractices.pdf

Primers on clinical research

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CISN.org: primer on research http://cisncancer.org/research/index.html

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Introduction to Pharmacokinetics and Pharmacodynamics ashp.org

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An advocate's notes on dose-finding studies Dose - the importance of getting it right

Terminology

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Glossary of lay terms for side effects http://humansubjects.stanford.edu/new/docs/glossary_definitions/lay_language.pdf

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Clinical trial terminology and acronyms  http://humansubjects.stanford.edu/research/documents/clinical_trial_terms.acronyms_AID01020.AID03022.pdf

 


The Ethical Principals of the Belmont Report

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Institutional Review Board Member Handbook 
Recommended book - Amazon.com  http://www.amazon.com/Institutional-Review-Board-Member-Handbook/dp/1449647448

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Principles of Clinical research based on the Belmont Report

Respect for persons (to insure self-determination)
autonomy, informed choice, voluntary, non-coercive, protect vulnerable, privacy and confidentiality

Beneficence (to protect well-being of subjects)
appropriate risk/benefit -- do not harm; maximize possible benefits and minimize possible harms

Justice (distribution of risk should be borne equally)
examine the characteristics of study population, ease of availability to participation, not exclude classes of individual

•  The principle of respect for persons includes two separate moral requirements:
1) the requirement to acknowledge autonomy and 2_ the requirement to protect those with diminished autonomy” (The Belmont Report)

In practice, this means that individuals have a right to decide for themselves whether to participate in research. You may not use information about people without first getting their informed consent. Special care must be taken with people who are unable to understand or who are particularly susceptible to coercion.

Beneficence

Two general rules apply:
(1) do not harm and
(2) maximize possible benefits and minimize possible harms.” (The Belmont Report)

In practice, this means that it is not OK to use people for research unless the research is likely to have some benefit. Furthermore, this benefit must outweigh the risks.

Justice

Justice requires that people be treated fairly. Researchers should not take from research participants without giving back:

“For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied.

Whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.”
 

 


Endpoints 

Ways to measure and compare outcomes, clinical benefit, in clinical trials  (DRAFT)

"For many centuries doctors used leeches and lancets to relieve patients of their blood. They KNEW bloodletting worked. EVERYBODY said it did. When you had a fever and the doctor bled you, you got better.  EVERYONE knew of a friend or relative who had been at death’s door until bloodletting cured him. Doctors could recount thousands of successful cases."

See also: When Laypersons Give Medical Advice

The lesson from history described above teaches us that the clinical observations of medical professionals cannot be relied upon when judging the efficacy of treatments.  Scientific methods are needed ... and have been the foundation of modern medicine.

The most common purpose of clinical trials is to test a study protocol in order to judge if it will provide meaningful clinical benefit - compared to the natural course of the disease or the disease treated differently.   Clinical benefit from a treatment is defined as an improvement in survival or quality of life.  It can be very challenging to demonstrate that a new treatment is an improvement over existing approaches.  For example the increase in response rate might be offset by impacts on quality of life or late toxicities. Comparing survival is the most objective way to compare outcomes ... but this requires large studies to account for differences in patient and disease characteristics - and, particularly for the indolent lymphomas, the influence of the tested treatments on response to subsequent therapies. 

Background for new advocates: 

Individual outcomes (even validated case reports) cannot be used as evidence of clinical benefit for the patient or others - because we cannot know how an individual would have done had they approached it differently - or if that patient's disease or risk factors are very much like other patients. 

So to judge how likely a new treatment will help others often requires controlled trials on large groups of patients with the same diagnosis, and similar risk factors.  The most objective evidence of how treatments compare will come from large studies that randomly assign patients to the different treatments to assure that the risk factors are balanced in the compared groups. 

Improved methods for evaluating the underlying biology of lymphoma will reveal new subtypes that were formerly considered one disease (such as Germinal B-Cell versus Activated B-Cell Diffuse Large B-cell Lymphoma).   So we can expect that patient selection for trials will increasingly be based on new tests that identify these subtypes -- instead of doing "all-comer" trials and that the increasing number of subtypes will increase the challenge of carrying out sufficiently powered clinical trials.

See also
The Problems with Testimonials AND Evaluating medical claims and data

Demonstrating in controlled clinical trials that a treatment improves overall survival is the most direct evidence that the treatment provides meaningful clinical benefit - as a difference in overall survival accounts for all effects of the treatments - good and bad, measured and not measured.   When two or more treatments provide the same or unknown survival benefit then the costs, and anticipated impacts on quality of life can determine which is superior.   

... However, there is a major issues with the survival endpoint, as it's not ethical to wait and see which approach to treatment improves the survival of two groups of patients.  Other treatments will be given to the patients at relapse, which confounds assessment of the survival endpoint.   So we need other ways to judge if a therapy reasonably predicts improved survival.  These measures are called surrogate endpoints.

Surrogate endpoints are like the parts of the elephant touched by the six blind men of Indostan - each sensation reveals a different aspect of the elephant - the toe, the ear, the trunk, but not the whole picture. 

The surrogate endpoints commonly used by investigators to measure outcomes in clinical trials are: tumor response rates, relapse rates, progression events, side effects rates, and the incidence of death.  The events are counted and plotted over time to see how often they occur and when - relative to the beginning or the end of treatment - or relative to the dose of a study drug in phase I testing.

The purpose of measuring endpoints is to compare the effects of the study drug - good and bad, on the patient or the disease.  Quality of life endpoints measure effects on the person - reported by the persons.  Disease event endpoints measure effects on the disease - reported by imaging.

 


EFFICACY ENDPOINTS

Must be weighed against the toxicities and risks of the intervention,
compared to the risk of the disease untreated or treated differently.

These terms are often used to evaluate and compare responses to therapies (outcomes) in clinical studies. They do not measure or predict individual outcomes, but are used to show how effective the treatment was for a given group of patients in a specific time interval. 

Actuarial Survival or Overall Survival (OS):
  A measures of the number of patient who are still alive following treatment in a fixed time interval.

Event free survival (EFS):  A measure of the number of patients who are still alive and have not had a relapse (the event) following treatment in a fixed time interval.   For example:  After 84 month the actuarial survival rate was 93.1% and event-free survival rate was 87.3% for a given therapy.  

Time to Progression
(TTP) is a measure used to estimate the response to treatment, generally in a clinical trial setting. As such it is often called an endpoint. It goes something like this: 

You get a baseline scan, usually CT, before treatment to measure tumor burden. A second CT after treatment measures the response, generally as a % of decrease in tumor burden (50% or greater being a Partial Response, and a CR indicating a Complete Response.) 

From that point the time interval between the response to treatment and the time the disease starts to show evidence of growing (or recurring if a CR), is Time To Progression. Of course how often CTs are taken can affect this measure greatly, so TTP can only be an estimate.

Progression free survival (PFS)
measures time to progression, relapse, and to death from any cause.  The rationale for including "death from any cause" - even if  not apparently related to the disease or treatment - is that it's not always possible to know what's related; and accidental or unrelated causes will balance out when comparing groups treated with different protocols. 

Disease Free Interval
is similar to Time To Progression, but it differs in that it only relates to complete responses (CRs), because "free" indicates no disease measurable. So only a person who has had a CR can be among those measured for disease free interval; for partial responders this term does not apply. 

Patient reported outcomes (PRO)
captured the burden of the disease or treatments directly from the patient -  outcomes that cannot be identified with standard tests, such as blood tests or imaging scans.

 


Low versus High-Risk Lymphoma

How much risk is acceptable for treatment (or in a clinical trial) can depend on the risk of the lymphoma and this can vary in the same diagnosis.  

The following charts show different survival plots from time of progression after R-CHOP – showing clearly that early progression of disease (POD of less than 1 year) is worse in respect to OS than late POD).  The red line in each chart shows the expected survival of the age-related normal population.  The dark lines with hatches show FL patients. 

Note that the two charts on the left show no difference from the expected survival of the normal population (red and dark lines overlap) when the Event Free Survival (EFS12) for FL patients after R-CHOP is 12 months or more.  

Contrast this with the two charts on the right side, where the red and dark lines separate in patients who did not achieve EFS12.

 

Evaluating Patient Reported Outcomes (PROs) -- gaining momentum

See also our topic page on PROS including Quality of Life
PROs may be especially important to capture for protocols that require long periods of treatment - maintenance.  When provided prior to treatment, the patient's report serves as the control when assessing treatment-related outcomes that affect quality of life - such as fatigue or pain.  

The Symptom Management and Health-related Quality of Life (SxQoL) Steering Committee has produced a number of webinars to assist investigators in Concept Design and using PROs in clinical Trials.  These webinars are listed below and are live on the NCI Division of Cancer Prevention Website: http://prevention.cancer.gov/news-events/events/videos/pro_symptommanagementwebinars.

NCI Shared Resources:

Symptom Management & Quality of Life Concept Design
This video covers a variety of practical considerations for developing a symptom management concept for clinical research.

Symptom Management & Quality of Life Concept Design
Airdate: 12/03/2013

Best Practices for Integrating Patient Reported Outcomes in Oncology Clinical Trials - The following webinar series is a collaboration of the International Society for Quality of Life Research and the National Cancer Institute. The videos in the series may be viewed independently or sequentially in the order listed below.

Session 1
David Cella, PhD presents
How to identify the PRO context for clinical trials and identify the relevant PRO domains
Air date: 09/04/2014

Session 2
Bryce B Reeve, PhD & Ethan M Basch, MD present
How to select the appropriate PRO measure
Air date: 09/03/2014

Session 3
Madeleine King, PhD, Michelle Naughton, PhD, & Lari Wenzel, PhD present
How to design a high quality study with PRO endpoints
Air date: 08/20/2014

Session 4
Amylou Dueck, PhD & Diane Fairclough, DrPH present
How to develop the statistical plan and sample size calculation for the PRO component of a clinical study
Air date: 08/19/2014

Session 5
Carol M Moinpour, PhD & Andrew Bottomley, PhD present
How to assure data quality for PROs in oncology clinical trials
Air date: 09/04/2014

Session 6
Michael Brundage MD & Melaine Calvert, PhD present
How to report PRO study findings from clinical trials
Air date: 08/19/2014

 

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June 12: Dr. Sandra Mitchell,
Capturing Symptom Burden and Treatment Tolerability in Cancer Clinical Trials,

Patient-Reported Outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE)  https://wiki.nci.nih.gov/pages/viewpage.action?pageId=133270269

The key elements of the PRO-CTCAE measurement system are exhibited, and the research challenges, gaps in knowledge, and the issues that will need to be resolved to fully implement this new approach are examined.


 

 
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For all medical concerns, you should always consult your doctor. 
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