Ethical considerations of neuro-oncology trial design in the era of precision medicine

Physicians must secure informed consent before sequencing patients’ tumors for entry into trials of targeted therapy. Informed consent requires physicians to explain details about the benefits and risks of a procedure or therapy accurately and understandably to patients. The rapidly changing landscape of genomic medicine requires physicians to understand the theory of precision medicine and be familiar with various therapies in order to inform patients of their options. Physicians differ in their levels of knowledge and experience with precision medicine, which may preclude the ability to provide adequate informed consent [11]. Even for physicians with knowledge on the topic, the limited health literacy of patients combined with complex medical jargon can opacify treatment options [12, 13]. The complexity of genomics in neuro-oncology and targeted therapy mechanisms may fortify the communication barriers that already exist between physicians and patients [8]. Furthermore, NGS exposes patients to discovering incidental genetic mutations not relevant to their entry into a trial. The content and format of informed consent must be adapted to overcome these challenges.

Informed consent requests must incorporate options for communicating incidental findings. In the clinical trial context, NGS will be used to screen for specific oncogenes that determine entry into a trial. It may also reveal the presence of incidental mutations in the same or different genes [14]. The outcry in response to the American College of Medical Genetics’ since rescinded recommendations to broaden screening for genomic variants in newborns without permission demonstrates the importance of respecting the right not to know about genetic mutations [15]. This same ethical principle applies in oncology, in which patients’ rights to not know about incidental mutations in their germline or tumor samples.

The four types of incidental findings in NGS are genetic variants that are medically actionable for the patient, medically actionable for the patient’s family but not the patient, associated with disease but not currently medically actionable, and of unknown significance [16]. Non-disclosure of incidental findings that are medically actionable may prevent interventions that would improve a patient’s outcomes health. Additionally, the discovery of incidental findings in this context can reveal germline mutations that lead to identification and management of family members at risk for cancer [17]. Consequently, NGS findings hold ethically salient consequences for family members who may tangentially learn medically relevant facts about their own genome that they did not consent to know. This phenomenon also affects the privacy of enrollees’ biological family members since the enrollee may learn about health risks in other family members by learning about their own genome. These findings may distress family members and subsequently affect familial social relationships in addition to potentially breaching the rights to not know and to privacy.

The disclosure of gene variants that accurately predict the development of diseases that cannot be prevented or managed may cause patient psychological distress, but allow them to adjust their life plans around this illness. Gene variants of unknown medical significance are also possible outcomes of NGS. Their disclosure likely carries no utility but may be stored in a medical record in case its significance becomes uncovered. Developing NGS technologies that only probe for mutations of interest for each individual trial circumvents the discovery of incidental findings altogether, but may be financially prohibitive and impedes the discovery of medically actionable variants. Each of these four potential scenarios must be clearly delineated in the informed consent process, and oversight committees should consider how to inform patients about the different types of incidental findings and how to create opt-in or opt-out systems for their disclosure.

The format in which informed consent is obtained must efficaciously communicate detailed descriptions of oncogenes of interest, targeted therapies, and potential incidental findings. The process must also be concise enough for patients to complete it without confusion or fatigue from the complex knowledge and different options they must weigh. Multidisciplinary teams can help design resources for patients and physicians to aid in this process; for example, genetic counselors may aid oncologists in communicating complex genetic information and implementing flexible consent processes [18]. Tiered informed consent approaches involve multiple stages of obtaining consent and provide patients the time to understand one element of the trial at a time [19]. The most central and necessary information about a trial is presented first, while less significant and more complex details like incidental findings are presented at an appropriate later time. Patients often have difficulty understanding and responding to the presence of mutations with unknown clinical significance, so any new informed consent structure must also include adequate educational resources to explain the uncertainty around these [20].

Each individual targeted therapy requires significant financial investment for research and development and is applicable to a narrow spectrum of patients, limiting its societal value [21]. An argument could be made that cheaper behavioral interventions that reduce the burden of oncological disease, such as smoking cessation, improved diet, and exercise, should be funded instead of more expensive targeted therapies. However, oncology should not be an “either-or” enterprise. As public health initiatives combat risk factors like cigarette smoking and obesity, the average lifespan continues to increase and age is an unmodifiable risk factor for many cancers. Also, many brain cancers, including medulloblastoma, glioblastoma, and atypical meningioma, do not have strongly associated modifiable risk factors. Even for those that do, the avoidance of risk factors does not guarantee the prevention of cancer. In addition, certain NGS technologies are becoming less expensive than routine MRIs, and smaller trials are less expensive to organize than RCTs.

There are also reasons to believe that despite the high up-front costs of a targeted precision therapy, it provides societal benefit beyond its immediate application as a therapy for a specific cancer. One such example is “drug repositioning”, the concept that drugs designed to target an aberrant protein in one cancer can be applied to other cancers with the same molecular disruption. For example, study of the V600E mutation in BRAF in melanoma led to the development of B-Raf inhibitors that years later, have shown potential efficacy in craniopharyngioma [5]. Early phase targeted therapy trials also contribute towards the general understanding of the significance of various mutations as potential oncogenes, which advances scientific knowledge in general. In any case, the majority of Americans support precision medicine initiatives [22].

RCTs often enroll dozens or hundreds of patients, providing high enough enrollment to allow for detailed statistical analysis of the effects of the new treatment. Smaller cohorts often have limited generalizability as the confidence interval for any measure of an outcome varies inversely with cohort size. In practical terms, a clinician determining whether to prescribe a new targeted therapy to a patient based on the results of a trial with two enrollees may be unable to determine whether their patient will respond similarly to those enrollees. If those enrollees also responded differently to the therapy despite having the same mutational profile, the clinician cannot accurately predict which enrollee the patient would respond more similarly to. Brain pathologies also face the unique challenge that therapeutics must cross the blood brain barrier.

The goal of precision medicine is to provide patient-specific therapies that maximize outcomes, including minimizing toxicity. However, even if multiple small trials show no evidence of toxicity for patients receiving a specific therapy, physicians cannot accurately determine potential toxicities without evidence from large and longitudinal cohort studies [23]. As with any therapeutic regimen characterized by uncertain efficacy and toxicity, this lack of knowledge should be communicated to patients. While a full understanding of the potential harms of a treatment that undergoes trials cannot be comprehensively known, physicians may weigh its potential benefits against proxy approximations of risk, such as the toxicity associated with other therapies that have the same pharmacological target or by extrapolation of a therapy’s toxicity profile in other cancers.

Institutional oversight is a requirement for clinical research. In the United States, any research that uses human test subjects requires Institutional Review Board (IRB) approval. The role of the IRB includes determining if there is enough preclinical evidence to justify a trial in humans.

The specificity of targeted therapies could increase the difficulty of accumulating sufficient preclinical evidence to justify any trial. In vivo testing would require the development of animal models of cancers that match the specificity of all study populations’ genomic signatures, which may be unfeasible. New experimentation protocols and emerging technologies such as ex vivo organoids and analytical data modeling can mitigate this problem, but ultimately, oversight committees must set strict and consistent evidential standards to warrant approval. Additionally, oversight committees have a role in ensuring that the therapeutics that were developed for other cancers and tested in neuro-oncology trials achieve therapeutic levels in the brain by crossing the blood brain barrier without increasing risk of systemic toxicity. Testing therapies that have not been proven to achieve therapeutic levels in the brain would bring further ethical challenges related to patient safety.

Last, the proliferation of early phase trials threatens to bring less oversight; it is much more manageable for an oversight committee to follow a large trial than many small trials, especially as the distinction between research and individualized care becomes less clear. Oversight committees will need to adapt to these anticipated changes to ensure appropriate adjustments that maintain sufficient oversight. While the function of these committees will remain the same, their structure should reflect the increasing number and complexity of these trials.

Neuro-oncologic patients enrolling in trials require protections given vulnerabilities inherent to brain disease and to potentially having refractory cancers. Brain pathologies and their therapies may subtly alter a patient’s decision-making capacity. The poor prognoses of many brain cancers may incentivize patients to explore experimental treatments. These problems are exacerbated for late-stage patients and those with refractory disease, such that these vulnerable patients may become the most eager group to join trials. This is especially problematic for Phase 1 trials, but also has implications for trials with therapeutic intent, which constitute the majority of precision medicine trials.

Equitable participant selection seeks to prevent the exploitation of vulnerable patients in clinical trials. Even though studies are being designed to test targeted treatments upfront, experimental targeted therapies are also tested in patients whose cancers remain refractory to traditional therapeutic modalities. Even though the primary goal of many precision medicine trials is related to care, at the same time, most investigators also have the goal to generate knowledge to improve management of future patients with similar disease profile as their enrollees. This implies that trial investigators should not continually seek the most desperate patients as enrollees only to then prioritize prescribing the tested therapy to healthier eligible patients. Ensuring that the characteristics of trial enrollees reflect their intended beneficiaries becomes more difficult to accomplish in small cohorts, so care must be taken to carefully define enrollee criteria and generalizability of a study.

The selection criteria for early phase targeted therapy trials will include specific genetic data that necessitate access to genetic sequencing technologies and the expertise to interpret genetic data. Patients of low socioeconomic status may not have equal access to these resources that are often located in advanced tertiary care institutions [8]. Consequently, both the enrollees and beneficiaries of these trials are more likely to be patients of high socioeconomic status, thereby excluding patients of low socioeconomic status. Furthermore, patients of different socioeconomic statuses face differential carcinogenic exposures, such as higher rates of cigarette smoking in poorer patients, which can lead to differential oncogenic changes.

It is important to note that just recruitment is a challenge in all clinical trials. The requirement of NGS technologies in addition to standard studies like MRI brings an additional impediment for patients of lower socioeconomic status. Therapies specific for genetic mutations that are more common in patients of low socioeconomic status due to certain environmental exposures may therefore never be developed, which would propagate these patients’ exclusion from precision medicine. Therefore, patients from lower socioeconomic backgrounds require increased protection to ensure their access to and representation within these trials [24, 25].

Genomic data gathered for these trials might also risk unfair treatment of enrollees by societal actors. The Genetic Information Nondiscrimination Act enacted in 2008 provides broad prohibitions for health care insurance and employer from discriminating based on known genetic predispositions for future disease. It is not all-encompassing; for example, insurers may request genetic data to determine whether to cover certain procedures [26]. Despite these protections, many patients and even some physicians fear potential discrimination and do not know the rights they have over their genetic data [26, 27]. These fears may be augmented by H.R. 1313, a piece of legislation recently introduced in Congress that exempts employer wellness programs from “limitations under the Genetic Information Nondiscrimination Act of 2008 on collecting the genetic information of employees or family members of employees” [28]. Protections against genetic discrimination should remain to maintain just societal treatment for patients and their families and to maintain their privacy.