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Advocacy > Commentary > Patient Perspectives on Clinical Trial Design

Guidance for the Industry and FDA

Last update: 04/30/2013

What Patients are Looking for in Clinical Trials | Known Obstacles to Accrual in Clinical Trials 
 
Clinical Trial Design Components

Timely participation in studies is vital – delays are costly to sponsors and to patients. 
 
If patients fail to sign on in adequate numbers ... the assessment of the therapy will not be made
no matter how well the study is designed from the point of view of regulators and scientists. 
 
Indeed, the urgency of our situation requires that the protocol evaluation system becomes as efficient as it can be. 

At a Glance:
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Include patient consultants early in trial design. 

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Design study protocols that are in harmony with patient goals:
 
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Are predictive tests used to identify who is likely to benefit?

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Is the protocol a reasonable treatment choice?

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Is it as flexible as it can be?

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Does it avoid burning treatment bridges?


What Patients are Looking for in Clinical Trials 

The primary motivation of John or Mary is to choose the best possible treatment for the malignant cells growing within them. Choices will includes investigational therapies, especially when the patient has refractory disease or a type of cancer that cannot be cured with standard therapies.  The desire to survive and to continue to provide for loved ones is primary. The desire to contribute to scientific progress is secondary.

Treating physicians are the primary gate keepers, and they will ask: Is the protocol a reasonable treatment decision for my patient compared to all the available options?

Patients and community doctors will therefore carefully weigh all of the following when evaluating clinical trial protocols:

a)      the potential to cure or improve survival.

b)      how the protocol may limit future treatment options
      (They will want to avoid burning bridges.)

c)      the potential to manage the disease with less toxicity.
      (Ideal management protocols will not burn treatment bridges.)

d)      the toxicity profile
      (Transient toxicities are more acceptable than long term toxicities)
      (Toxicities are more acceptable when there’s a significant potential to cure.)
      (Patients want to avoid toxicities that preclude subsequent treatment options.)

e)      the potential to overcome drug resistance.
      (Relevant in palliative/refractory setting.)

f)        the potential to improve quality of life and performance. 
 


Quality of Life (QOL) Endpoints - Often a missed opportunity:

New therapies that may maintain or improve quality of life are of vital importance to patients. Therefore, we encourage drug sponsors to include assessments of QOL.  Within are resources and discussions related to this very important, but not often used, endpoint. 

"Findings from QOL research can inform clinical care by providing information about the likely impact of disease and its treatment on functioning and well-being, identifying common problems, and developing effective interventions to deal with these problems. The routine assessment of QOL may also have clinical uses at the individual patient level." 3

  1. Quality of Life Assessment in Clinical Trials - PPT 
  2. Training - biostat.wisc.edu -pdf 
  3. Assessing quality of life in research and clinical practice.Oncology (Huntingt). 
    2002 Sep;16(9 Suppl 10):133-9. Review. PMID: 12380963 | Abstracts
  4. Instruments for measuring QOL - abstracts | FACT instrument | FACT sample - PDF
  5. End Points and United States Food and Drug Administration
    Approval of Oncology Drugs - By John R. Johnson, Grant Williams, and Richard Pazdur - FDA - PDF 

    Quality of life. Although many of the 53 marketing application approvals that were based on nonsurvival end points used surrogate end points for a better life, no approvals were based on instruments measuring health-related quality of life. Although quality-of-life (QOL) assessments using global QOL instruments often have been submitted in oncology drug applications, this aspect of the clinical trials has generally not been well conducted. 

    Problems have usually included unblinded assessment, large amounts of missing data, and poorly defined prospective analytic plans. 

    Applications including QOL claims should use QOL instruments validated for the intended purpose: to measure QOL differences in randomized studies of patients with a specific cancer type. Changes in QOL scores should be defined in clinically meaningful terms. QOL data are most credible when patients and investigators are blinded to treatment assignment, when QOL findings are duplicated in trials using the same instrument, and when QOL analytic plans are prospectively detailed.9 
  6. Commentary Concerning Demonstration of Safety and Efficacy of Investigational Anticancer Agents in Clinical Trials - ctep.cancer.gov 

Response Rate [& Quality of Life]: It may be argued that virtually any drug should be considered effective if it produces a response rate above some arbitrary level (e.g., 20% for may solid tumors). If one were to accept such thresholds, it seems clear that the level should be a function of the tumor type and stage. For example, the threshold response rate for previously untreated indolent lymphoma might be considerably higher than that for renal cell carcinoma or melanoma. In general, however, it is not meaningful to consider response rate without also considering duration of response, the general level of toxicity, and effects on QOL. - ctep.cancer.gov pdf, page 4.

Beneficial Effects on Disease-Related Symptoms and/or Quality of Life (QOL): 
"QOL may be improved if treatment decreases symptoms of disease, as measured directly or with validated QOL instruments. Parameters of QOL could include improvement in tumor-related signs or symptoms, improved physical or psycho logic function, decreased reliance on medical support, gain in lean body mass, etc. The usefulness of QOL instruments in demonstrating patient improvement is a matter of considerable interest. Improved QOL may be demonstrated in two kinds of studies:"  

Comparison with control therapy in a Randomized, Controlled Trial

Comparison of patient's post treatment status with pretreatment status 


Patient Perspectives on survival endpoint for indolent cancers

We recognize that improved survival is the ultimate goal for patients and the most significant measure of clinical benefit. However, patients with indolent cancers will have opportunity to use additional therapies, including other investigational therapies when they progress or go off study, and that this will confound the assessment of survival.  

Therefore we believe that the survival endpoint is not a practical way to evaluate therapies for indolent lymphomas, and use of this endpoint can lead to unethical trial designs and problems with enrollment. For example, it can lead to protocols that do not include a crossover provisions, which would allow patients in the control arm the option of receiving the investigational agent when they progress or relapse.  Not providing a crossover provision raises many ethical questions, and can have a negative impact on trial enrollment.

FDA on evaluation of drugs with favorable toxicity profiles: 

“47% of regular oncology drug approvals had response rate or time to tumor progression as the primary or coprimary end point in trials supporting approval.” …

… given the favorable toxicity profiles associated with hormonal drugs compared to conventional cytotoxic agents, Response Rate and Time to Progression are considered adequate surrogates for a better life.”  

Source: Endpoints and US FDA Approval of Oncology Drugs, April 2003
 

 


Patient Perspectives on Randomized Studies:  

In general, patients feel unlucky and will judge the merits of participating in a randomized study by anticipating that they will receive the control, and then evaluating how good or bad that might be.  

We believe this ought to be the criteria for judging the suitability of a protocol by the patient’s treating physicians as well.

From our perspective, both arms of a study should be considered equivalent in potential.  When this is not possible – and especially when survival is not an endpoint – a crossover provision should be included. 

 


Getting Creative Early: Test immune-based therapies for patients in watchful waiting status

We believe that patients in watchful waiting status provides an important opportunity to test immune-based therapies that have good toxicity profiles. So we encourage drug sponsors to seize this opportunity by including this group in study designs.

Opportunities: 

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Better immune competence

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Less tumor burden

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Less prior exposure to toxic treatments

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Potential to improve quality of life

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Potential to learn without precluding standard treatment options

Patients with indolent lymphomas are keen to try frontline immune-based therapies, and avoid chemotherapy.  When a cancer is not curative with standard therapies, it is logical and reasonable, we think, to start with the least toxic approaches first.

From our perspective the ideal time to get creative is early when a response to treatment is not required and when we are more likely to benefit from the approach.

 


Patients have technical and ethical concerns about placebo vaccines.

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Is the resection of a lymph node an ethical way to blind a study?

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Can exposing patients to the adjuvants (conjugates) in a placebo vaccine preclude them from 
benefiting from the cancer vaccine in the future?

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Can the pretreatments do the same? 

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Can crossover provisions be used to relieve these concerns? 

From our perspective, placebo vaccines are bound to slow accrual and delay assessments.


Known Obstacles to Accrual in Clinical Trials
 

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Lack of appropriate clinical trials – for example, very aggressive protocols.
 
40% of cancer patients who have access to and are eligible for a clinical trial, decline to participate.  
*Comis RL, Miller JD et al. JClinOncol 21:830-835; 2003  
 
See What Patients are Looking for in Clinical Trials above.

 

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Excessive protocol eligibility restrictions.
 

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Patients may not be aware of medical developments and may be less inclined to seek out clinical trials  - 
elderly patients in particular.
 

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Patients and health providers may not be aware of the patient’s life expectancy.
 

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Patients may not be aware of the true risks of the disease, the limitations of standard therapies, or the potential advantages of emerging therapies.
 

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Patients may have difficulty understanding complex protocols, and will avoid what they do not understand.
 

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Patients may lack access to oncology centers that conduct clinical trials.
 

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Patients confusion about research and medical care, and study procedures.
 

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Community doctors may not be aware of clinical trials, and which investigational therapies are most appropriate for their patients.
 

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Competition for patients among drug sponsors reduces the patient pool.
 

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Lack of financial, logistic and social support for participation in clinical trials – including insurance coverage for medical tests associated with studies.
 

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Patients might be too sick to evaluate a study, or complete the applications, or too ill to travel. 
 

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Patients may fear some tests, such as bone marrow biopsies.
 

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For biotherapies there could be a need to recruit patients who are not in need of immediate treatment. 
This group will be more cautious and selective.
 

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For indolent cancers, there could be a need to enroll larger numbers of patients in order to get 
statistically significant data.


 
Other Clinical Trial Components

Safer ways to monitor response?

There is a growing concern about repeated use of CT in clinical trials.  Patients are now aware that x-ray exposures for CT are very high (see below) and trials that monitor for time to progression require frequent exposures.  This concern is most relevant to young patients with indolent cancers. See http://www.fda.gov/cdrh/ct/risks.html#dose

CT abdomen

10.0 mSv

500  chest xrays

= 3.3 years background. exposure

Bone marrow biopsy

We understand that there may be important reasons for giving this test in some protocols, but drug sponsors and the FDA should be aware that this test in particular can have a negative impact on trial enrollment.

Assessment of response for lymphomas

We have a general concern that CT imaging cannot distinguish between inflammation and true progression in lymphoma. Therefore, the criterion used to remove a subject from a  study based on a percentage increase in the size of lymph nodes is troubling, particularly when the the baseline lymphadenopathy is small. Consider also that the angle of the scan can sometimes affect the measure. Therefore, we urge a lymphoma-specific addendum to the WGR Criteria to include corroborating indications when evaluating response to treatment. 

Can study protocols be more flexible for immune-based therapies?

Can we adapt a protocol to account for patient differences? For example, can alternative methods be tried when the first way fails to induce an immune response?

Can protocols adapt to patient differences?

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Immune competence and characteristics

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Clinically unique disease & response to treatment

 

Can alternative methods be tried when the first way does not achieve an immune response?

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Different number or timing of injections?

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Intratumoral administration?

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Alternative adjuvants?

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Booster vaccines?

 

Emerging tests will increase patient confidence in clinical trials and incentives to participate:

Increasing confidence: DNA typing and biomarkers that may predict response to the investigational agent or the pretreatment.

Increasing incentives: Tests that may help predict the clinical course of the patient’s disease, or likely response to standard treatments.

Targeted therapies may require pursuit of orphan drug status:

It is tragic when a promising drug is dropped when studies fail to identify who a drug is for. For example, when a trial for a low toxic treatment results in a 10% response rate.

We have about 500,000 people living with lymphoma in the US alone, and 10% of them would be ~ 50,000 people. That's a lot of folks.

So we conclude that we must begin testing some new drugs in new ways:

1) Get snap-frozen tissue from pts & evaluate gene expression using microarrays, as well as and immune and metabolic profiles using other emerging tests.

2) Do the normal exploratory small trials to determine safety, dosing, and efficacy.

3) Correlate responders in step 2 to profiles identified in step 1.

4) If you find a correlation, select the patients with the optimal profiles for the next study.

If you've got a good drug, you will need to run much smaller studies to prove it because 18 of 20 responses could well be statistically significant, especially if the therapy has low toxicity. Importantly, patients will want to participate because the predictive tests make it a more reasonable try.

Presently, we have a crisis. We have more new agents and ideas than patients to test them on. Competition for patients is fierce, so much so that drug sponsors are now asking patient advocates what kinds of trials we want. 

If in our system we can only approve drugs that work for a high percentage of patients (using broadly/ill-defined definitions of lymphoma), we end up with what we have: plenty of one-size-fits-all drugs - which have lots of toxicity (needed to get the desired response rates) - which often offset the clinical value of the responses considerably. 

We believe that drug sponsors need to explore filing for orphan drug status for the discovered clinical subtypes of lymphoma.  

"The Orphan Drug Act defines orphan products as ones used to treat diseases or conditions affecting fewer than 200,000 persons in the United States. Such small patient populations reduce profit potential for sponsors, so the act grants special privileges and marketing incentives. " See http://www.fda.gov/fdac/special/newdrug/orphan.html


 
Compassionate & Expanded Use of Investigational Therapies

See Patient Access to Emerging Therapies

 

 
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professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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