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Trial types by clinical circumstance - advocacy suggestions for researchers

Last update: 02/19/2016

Clinical Circumstances and Related Feasible Trial Designs

The Purposes and Challenges of Clinical Research

The purpose of clinical research is to advance clinical practice so that future patients can live better and longer.  Clinical trials also have the potential to meet the clinical needs of the participants of a study, else the intervention should not be studied.  Increasingly, a purpose of clinical research includes the testing of tests (biomarkers) that may predict who is likely to benefit from a given drug or combination approach to treatment before the treatment is given to future patients.

Here we ask the people afflicted with the disease to be test pilots in order to explore new options (in early phase studies) or to validate that a new approach improve outcomes (in phase III controlled studies).   To avoid undue influence, we cannot compensate the participants of the clinical studies ... who are the true heroes of this noble mission.

Here we remind the patient community and clinical investigators that the feasibility of achieving full accrual will depend on numerous elements:  the trial design (comparative versus single-arm, biopsies and other extra tests and procedures), competing trials, the actual and perceived risk of the approach (including the control), and what is available for treatment outside of the trial. 

To get the job done (and to be worth doing) the study must be good science (able to answer the question reliably) AND also good medicine: perceived to be an appropriate therapeutic decision for the patients.

Here we offer patient perspectives on how we might meet this challenge -- specific to the participant's clinical circumstance.  Abbreviations used within: RCT Randomized Controlled Trial | CR - Complete response endpoint
PFS - Progression Free Survival (essentially: time to progression when no difference in survival)
Crossover - allowing participants to change arms on progression.

Clinical Circumstances and Related Feasible Trial Designs

What follows are our suggestions for trial designs and approaches that may be most feasible for common clinical circumstances, such as:

Watchful waiting asymptomatic, indolent with low tumor burden
Consider novel approaches with low anticipated risks, such as building on Rituximab monotherapy

RCT design can be feasible particularly with crossover since the anticipated outcome for this approach is not curative. However, what is discovered in such studies could then be applied to approaches with curative intent in subsequent studies.

Patients may not be willing to accept high risk investigational protocols in this setting, given the unknown and often low risk of the disease.

Examples: [placeholder]

Indolent lymphoma, previously untreated, with need to treat - all comer trial
(standard therapy + immunotherapy consolidation)
RCT could be feasible due to uncertainty about value of addition of any study drug on OS in this population
Consider setting high bar for PFS due to uncertainty that PFS predicts OS in this setting.
Consider serial MRD status if it can aid in interpretation of quality of response -- to validate it as predictive of OS.

Patients with indolent lymphoma may not be willing to take large risks in this setting, given the unknown and often low risk of the disease. Immunotherapy consolidation is recommended for study due to the improved durability associated with responses to immunotherapy - extending and continuing beyond duration of the treatment.

Aggressive lymphoma, previously untreated
(standard therapy + targeted therapy and immunotherapy consolidation)
RCT seems feasible if the study builds on curative standard therapy

Patients may be willing to accept additional risks, given the poor outcomes and toxicity of treatments that are needed if they relapse from standard approach, which is not uncommon.

Treatment-refractory, aggressive / including transformed
(combination therapy with agents having new mechanisms of action with potential to induce durable remissions)
CR seems the key endpoint - needed for meaningful benefit in this setting, not ORR.
Stable disease achieved with well-tolerated maintenance regimens will also be of value to patients in this circumstance.
RCT not appropriate / feasible if standard approach is ineffective
Adaptive study design could be important tool for settings where there is no satisfactory standard approach.

Patients may be willing to take more risks, given the very high risk of the disease in this setting.


Related Issues and Resources

Comment from advisor:

My spouse has aggressive follicular lymphoma. She would not even consider a Phase 3 trial unless the trial provided cross-over. For her fourth treatment  she chose Idelalisib/rituximab following a Phase 3 trial protocol but outside the trial since it did not offer crossover. 
Mandatory biopsies can be a barrier to enrollment.  This is most appropriate when the test is integral to the study question - cannot be answered without the test on the sample when the test is validated.
Optional biopsies may be feasible to get if clinically informative tests are also done on the sample (in addition to the research-related tests) to guide care of the patient outside of the trial.
Berry group:
What Clinicians Should Know About Adaptive Clinical Trials - YouTube http://bit.ly/1PrQ7ob
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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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