Ethical Considerations of Neuro-oncology Trial Design in the Era of Precision Medicine

Abstract

priority as part of a major US public health initiative. This new paradigm builds on the idea that cancers that harbor certain oncogenic mutations may be particularly susceptible to therapies that specifically target the aberrant proteins created by these mutations. As next-generation sequencing techniques have begun to uncover some of the mutations that drive the formation and growth of various cancers, applying this new therapeutic framework has the potential to revolutionize cancer management.The last decade has seen many innovations in the usage of targeted therapies. Vemurafenib, a targeted kinase inhibitor of the B-Raf protein variant produced by a V600E point mutation in BRAF, has been shown to reduce tumor burden and to improve overall survival in melanoma patients [1]. Similarly, gefitinib and erlotinib prolong survival for patients with non-small cell lung cancer by inhibiting overactive epidermal growth factor receptor caused by activating mutations in EGFR [2,3]. Precision medicine potentially has tremendous applicability in neuro-oncology and will allow patients to receive individualized therapies that target the genetic mutations underlying their diseases [4]. Indeed, early phase n-of-1 and small cohort investigational trials studies have already begun to demonstrate the potential of precision medicine in neuro-oncology [5][6][7].The successes and potential of precision medicine have also introduced new challenges not only related to clinical care, but also to ethics of clinical research. While there remains little doubt of the potential improvements in efficacy with precision medicine, characterizing and understanding these challenges can uphold the standards of patient autonomy, respect, and protection. In this discussion, we review pertinent ethical challenges to early phase clinical trials in precision medicine. AbstractThe field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges. We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design.

Patients’ and professionals’ views related to ethical issues in precision medicine: a mixed research synthesis

“…However, there is more doubt among professionals as to whether patients actually benefit from PM, which may be related to the fact that there is less evidence for positive effects of PM than in conventional medicine. The high specificity and costs of therapies mean that drugs are tested in smaller clinical trials rather than in large randomized controlled trials and even if several small trials have shown no risks, a level of uncertainty remains [ 10 ]. It is quite understandable that HCPs, whose training has so far been oriented on the ideal of evidence-based medicine, have more doubts here.…”

“…Experiencing a potential risk of illness can be a considerable strain on people, especially if the illness is incurable. However, avoiding telling patients about their genetic disposition for a treatable disease can also be harmful, as it deprives patients and their families of the opportunity for prevention and screening [ 10 ]. Therefore, for each genetic test, the patient's preferences regarding the information about disease risks should be respected, as already contained in existing legislation in some nations [ 128 ].…”

“…In addition, incidental findings associated with genetic traits of unknown clinical significance or findings of misattributed parentage [ 8 ] are problematic, because communicating these findings to patients and their families can also trigger stress and affect family relationships. By obtaining informed consent, the information on possible incidental findings should be kept short and concise so that patients understand the complex issue and are not confused by the various options for decision [ 10 ]. The possibility of re-contacting the patient is seen as a moral obligation if findings of previously unknown clinical significance can be better understood in the future and linked to therapeutic options [ 9 ].…”

“…Many ethical challenges regarding PM have already been reported. In addition to ethical issues concerning the massive data storage and data sharing, these challenges include: a possible discrimination by insurance companies and employers [ 6 ] discrimination in access to PM [ 6 , 7 ] incidental findings in genetic testing [ 8 ] the lack of health literacy or “genetic literacy” for obtaining informed consent [ 9 ] the lack of scientific evidence of the efficacy and tolerability of treatments [ 10 ] the possibility of changing the patient-physician relationship by focusing on data [ 11 , 12 ] and the increasing expectation on patients to contribute with data, time, effort and self-care [ 7 ]. …”