Psychiatric and central nervous system trials have been making headlines as ‘next-generation’ drugs are reaching clinical stage research. When it comes to patient recruitment, trial adherence, and informed consent, these trials become increasingly complex to navigate.
Patients play a vital role in clinical trials as they enable insights into the nuances of the disease. Technological developments, like AI, can ease the difficulties of clinical trials in special patient populations, and provide greater opportunities for patient-centricity.
Outsourcing-Pharma (OSP) spoke to Andreas Schreiner (AS), executive director of medical affairs neuroscience and analgesia at Premier Research, who provided some insights into trial complexities and new drug delivery formulations. In part I of this two-part piece, Schreiner highlights the logistics behind these clinical trials specifically in patients with schizophrenia.
OSP: What are the unique challenges to patient recruitment in mental illnesses?
AS: Many patients with schizophrenia have an inherent paranoia and distrust of medications, providers, and the healthcare system, and invasive treatments such as injections [an aspect of a clinical trial currently recruiting] may exacerbate these feelings.
Another challenge that sponsors of schizophrenia trials face is being able to recruit the right patients. While it is thought that those patients who are non-adherent are those most likely to benefit. Studies have shown that these patients are also least likely to volunteer for studies.
OSP: What about informed consent?
AS: Research involving individuals with schizophrenia may pose unique challenges related to obtaining informed consent. Given fluctuations in the positive, negative, and cognitive symptoms of the condition over time, a patient’s capacity to consent may fluctuate as well but does not necessarily preclude them from giving informed consent.
OSP: What role do caregivers play in recruitment?
AS: Sponsors should also keep in mind that family and friends may play an important role in influencing a patient’s decision to participate in a placebo-controlled trial (PCT), especially if they are concerned about the possible risk of relapse.
OSP: Is giving a placebo to a schizophrenic patient inappropriate?
AS: Within the field, there is heavy debate over the use of PCTs [placebo-controlled trials] in schizophrenia. While PCTs are the gold standard for demonstrating the efficacy of new treatments, there are ethical issues surrounding the use of placebo controls when efficacious treatments are already available.
The selection of a PCT design may also impact retention and, ultimately, data quality. Interestingly, studies have shown that dropout rate is influenced more by trial design (active-controlled trial vs. PCT) than by the class or identity of the medication being studied.
OSP: What are the medical and ethical considerations?
AS: Those who object to PCTs argue that these studies put participants at an increased risk of relapse, which subsequently increases the risk of long-term disability, morbidity, and mortality. Some PCTs have established relapse as the primary endpoint for patients in the placebo arm of the study. Providers might avoid such trials not only on ethical grounds but also due to the perceived risk that a stable patient could be randomized to the placebo arm, putting their disease stability in jeopardy.
Placebo-controlled trials may also be difficult due to an increased likelihood that providers will be more willing to pull patients out of a trial if they perceive a patient’s clinical course has changed for the worse (even if these changes are typical of normal symptom variation).
OSP: What are some ways in which to design a clinical trial for mental illness treatment that doesn’t involve placebos?
AS: Statistically, ACTs could be used more if studies were powered correctly and were analyzed as non-inferiority trials. Providers are also more likely to refer patients to clinical trials with study protocols that help limit the risk of relapse.
To optimize a study design for schizophrenia, sponsors should consider: Using as little placebo as possible, or allowing for imbalanced randomization so more patients receive the active drug. Allowing for sufficient rescue medication. Closely monitoring patients in the clinical trial through clinic visits or phone calls. Establishing a conservative definition for relapse. And, enrolling a patient population that is closer to the one that would ultimately benefit from the investigative treatment that is a non-adherent and less adherent group, to increase effect size.
OSP: How are small biotech’s driving change in psychiatric research?
AS: Small and mid-size biotech and pharmaceutical companies are currently exploring treatments with new mechanisms of action (MoA) which are considerably different from the traditional dopamine or dopamine/serotonin MoA.
Over the last couple of years many big pharmaceutical companies have withdrawn from neuroscience research, so in the upcoming years, a lot of important and innovative research will rely on the activities of those small and mid-size biotech and pharmaceutical companies.