Examining the Impact of Real-World Evidence on Medical Product Development Proceedings of a Workshop Series (2019) / Chapter Skim
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7 How Tightly Should Investigators Attempt to Control or Restrict Treatment Quality in a Pragmatic or Real-World Trial?
7 How Tightly Should Investigators Attempt to Control or Restrict Treatment Quality in a Pragmatic or Real-World Trial?
Pages 99-116
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From page 99... ...
• When considering treatment restriction in real-world trials, researchers may consider a specific set of questions or catego ries for consideration in order to plan a trial that answers the research question and honors research participant safety and autonomy. (Alphs, Stein)
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Gregory Simon noted, "We're talking about real-world treatment, and by that we mean studying treatments with typical providers and typical patients, accepting that there will be highly variable quality of, and adherence to, treatment." ILLUSTRATIVE EXAMPLES To explore the issues surrounding treatment quality in real-world trials, speakers at the second and third workshops presented case studies as illustrative examples of the considerations that go into treatment quality control and restriction. Lithium for Suicide Prevention For more than two decades, lithium has been proposed as a treatment to prevent suicide in patients with bipolar disorder and major depression, said Ira Katz, senior consultant for program evaluation at the U.S.
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From page 101... ...
Researchers expected to see a far higher number during the course of the clinical trial because they assumed that many suicide attempts that were not documented in the medical record would be captured with the assessments included in the RCT protocol. However, experience in the study has been consistent with the 15 percent rate, said Katz, which was "really surprising and a puzzle." After examination of other data, the researchers determined that what was likely happening was a counterbalancing effect: The suicide attempt rate was probably decreased due to filtering out from the RCT process, and at the same time, it was probably increased due to the RCT protocol that uncovered suicide attempts.
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From page 102... ...
After the research began, they discovered that 30 percent of otherwise eligible patients were excluded specifically because they were on ACE inhibitors. Katz and his colleagues successfully argued to the IRB that these patients had to be included if the trial participants were going to be a representative sample of the true patient population.
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From page 103... ...
InterSePT: Clozapine Versus Olanzapine for Suicide Prevention The first case study was an international trial that compared the use of clozapine and olanzapine for suicide prevention in patients with schizo phrenia or schizoaffective disorder. Patients with these disorders, said Alphs, are at high risk of suicide behavior, with a lifetime risk of suicide attempts at 25 to 50 percent and a lifetime risk of death by suicide at 5 percent.
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Because the potential outcomes were so severe, and ethical considerations required that the research design minimize suicide attempts and deaths, the patients' clinicians needed the knowledge of treatment to flexibly manage their patients should they become suicidal.
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. Significantly fewer patients in the clozapine treatment arm attempted suicide, required hospitalization, required treatment with concomitant drugs to prevent suicide, or died by suicide.
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From page 106... ...
The mean days to treatment failure were nearly 6 months more for patients who received the injectable antipsychotic treatment. Using results from this study, the researchers applied economic modeling to stable schizophrenic Medicaid patients with similar clinical characteristics to predict health economic outcomes.
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From page 107... ...
Session moderator Jennifer Graff, vice president of comparative effectiveness research at the National Pharmaceutical Council, encouraged workshop participants to consider how much variation could be desired or accepted in terms of treatment, setting, or provider, and what elements of trial participant safety and autonomy could be most important. She asked, "What is our obligation to deliver safe care if we are watching what happens in the real world?
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of resources/experience/expertise are now present in the care settings in which results of this trial will be applied? What level(s)
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Is there some minimal or floor level of treatment quality necessary to assure participant safety? FIGURE 7-2 Decision aid on questions to consider regarding participant safety and investigator control of treatments in a trial taking place in a community care setting.
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From page 110... ...
It was created in 2015 with support from the Patient-Centered Outcomes Research Institute, and is 1 of 33 networks within PCORnet, the National Patient-Centered Clinical Research Network. ArthritisPower has a smartphone app that is used to collect patient-reported outcomes (PROs)
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From page 111... ...
. CONTEXT OF THE DECISION As with any decision about how to design a study, said Peter Stein, deputy director of the Office of New Drugs at FDA's Center for Drug Evaluation and Research, the first consideration is the context of the decision to be made: What is the research question?
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From page 112... ...
For example, if the research question is how an intervention works in an expanded population in the real world, a trial in which patient treatment was tightly controlled might not generate generalizable evidence about real-world usage. Stein pointed to the study on oral versus injectable antipsychotics presented by Alphs, and said that the decisions about patient treatment in this case were based on what the study sought to discover.
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From page 113... ...
OBLIGATION TO PATIENTS Investigators, said Simon, have "dual interests." Investigators have a duty to uphold the protocol of a trial to ensure that the research question is answered; meanwhile, they also have a duty to the safety and well-being of participants. These dual interests can sometimes conflict, and as Simon noted, "We want to make sure the duty to the participant always trumps the duty to the protocol." Safety Monitoring Researchers have an obligation to ensure that participants in research are receiving treatment that is appropriate for their condition, and that the treatments are safe, said Alphs.
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From page 114... ...
Now, CIOMS has revised its guidelines to a "ustice-based approach," which encourages the participation of vulnerable j patients so that research can generate the information necessary to treat these populations. Simon concluded, "Unless we welcome in the way the real world works, we are never going to answer these questions." Standard of Care Califf said that when researchers are designing trials, they have to decide on one of three options for the treatment for the control group: the
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From page 115... ...
This variation can make it challenging to detect whether and to what extent a new treatment is better than the standard. Simon asked Katz about balancing the needs of both the research question and the extremely vulnerable patients in the study on lithium for suicide prevention.
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From page 116... ...
116 IMPACT OF RWE ON MEDICAL PRODUCT DEVELOPMENT treatment decisions, he said. Evidence from observational data can be used, said Berger, along with evidence from RCTs or pragmatic clinical trials to build a "corpus of evidence" about a treatment.
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