UNDER DEVELOPMENT - DRAFT
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
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
approaches with low anticipated risks, such as building on Rituximab
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.
not be willing to accept high risk investigational protocols in this
unknown and often low risk of the disease.
Indolent lymphoma, previously untreated,
with need to treat - all comer
(standard therapy + immunotherapy consolidation)
RCT could be feasible due to uncertainty about value of addition
of any study drug on OS in this population
high bar for PFS due to uncertainty that PFS predicts OS in this
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
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
with agents having new mechanisms of action with potential to induce durable
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
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
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.
What Clinicians Should Know About Adaptive Clinical
Trials - YouTube