Bringing Advanced Therapies for Parkinson’s Disease to the Clinic: An Analysis of Ethical Issues

INTRODUCTION

Advanced therapies for Parkinson’s disease (PD) include a broad range of treatments, each presenting specific ethical challenges. Some of these therapies, such as device-aided therapies, are established and in clinical use. Others, based on advanced therapeutic medicinal products (ATMPs), are still in early stage of clinical trials.

PD affects patients of all social backgrounds worldwide [1], their caregivers, and society in general [2]. It is one of the leading causes of disability in humans, the most common serious movement disorder in the world affecting 1%of adults older than 60 [3], and is increasing in incidence due to an aging population [4, 5]. It significantly reduces quality of life both for patients and families supporting them: it is a progressive course towards the loss of patient’s independence, dignity and, eventually, life itself [2].

This paper reviews some common ethical challenges for clinicians and investigators contemplating applying device-aided therapies and ATMPs for PD and lists some practical suggestions in these different contexts. While many of the issues raised in this paper are relevant to efforts being undertaken across the globe, EU regulatory examples are chosen to illustrate the ATMP-related ethical challenges.

ADVANCED THERAPIES: A BROAD CATEGORY

Advanced therapies for PD can be divided into 1) symptomatic treatments (used clinically as conventional therapies) and 2) disease-modifying treatments (still in the experimental stage). The first category, although life-quality improving, does not slow or stop the progressive course of PD [3, 5] and develops adverse effects over time [3]. Here belong device-aided therapies, indicated for improvement of health-related quality of life when after a few years of peroral/transdermal PD medications a majority of patients develop motor fluctuations and dyskinesias [6, 7] despite more frequent dosing [7]. Device-aided therapies do not prevent or replace the progressive loss of mDA neurons in PD [5]. The second category, contrary to the first, aims at modifying the progression of PD. Here belong ATMP-based therapies, expected to offer potential cure, but still some years off and the efficacy of which cannot be guaranteed [8]. Both categories include a number of different treatments, the main features of which are summarised in Table 1.

SELECTED ETHICAL CHALLENGES IN ADMINISTERING DEVICE-AIDED THERAPIES

The main purpose of device-aided therapies is to improve the patients’ quality of life by reducing motor symptoms [6, 14]. For example, infusion therapies reduce “off time” (time with PD symptoms) [13] by at least 60%–65%[6]. Device-aided therapies are not risk-free. In DBS, electrodes are surgically implanted into the subthalamic nucleus and globus pallidus—a procedure associated with adverse effects such as the worsening of cognitive, motor or psychiatric symptoms and cerebral hemorrhages or stroke [16]. The mechanisms behind the underlying efficacy of DBS are not well understood [17], and unexpected harms can sometimes be induced [18]. Although DBS is considered a “reversible” treatment, there are concerns that non-stimulation-dependent effects of DBS can occur [19]. In infusion therapies, complications mainly relate to infusion equipment and the establishment of the percutaneous endoscopic gastrostomy, or local inflammation at infusion site [6]. Many of these risks affect mainly the patient. But risks like worsening cognitive or psychiatric symptoms affect both the patient and the patient’s caretaker or family.

In order to be able to improve a patient’s health-related quality of life, it is essential to first identify what is important to that particular patient. The ethical challenge here is manifold, e.g.: 1) balancing the patient’s best interests against those of the caretaker without compromising the patient’s interests, in treatments with high potential to affect patients’ caretakers; 2) helping the patient make the best decision, when it comes to early decisions about advanced therapies; and 3) making personalised recommendations considering that patient’s values and aims over time.

For clinicians, the first ethical challenge starts with identifying “target patients”—should they consider the patient alone or the patient-caregiver “tandem”? Different advanced therapies suit different types of patients and vary in effectiveness on health-related quality of life, side effects and safety. These effects may be of different value to individual patients who choose these therapies to improve their quality of life, a highly personal and value-laden concept [20]. Therefore, choosing the right type of therapies for the right type of patients from the clinical perspective is only half the job; knowing patients’ preferences and goals [20] is as important as the clinical parameters. Should the caregivers’ perspective also be considered, especially when their daily lives are also affected by the care they are providing, as is often the case with family members and other non-professional caregivers? Some argue that knowing the family’s goals is important to clarify and align expectations of patients and caregivers with what can be achieved from a particular type of advanced therapy [20, 21]. Knowing the caretakers’ capabilities and limitations is equally important—what could actually work for that family or other persons caring for the patient? Agreeing on treatment decisions jointly between PD patients, their caregivers and health care professionals can optimise individual therapy [21].

Why is the caregivers’ perspective important? For the first, caregivers play an important role in supporting patients: from assistance with daily life activities and management of PD-related tasks (appointments, medication) to treatment decisions [21]. The family is also an important pillar in patient’s process of adapting to the disease and integrating it into daily living [22]. Secondly, caregivers are affected by treatment options chosen. PD implies emotional, cognitive and personality changes, influencing the patient’s behaviour in daily situations [23] which affects caregivers. For example, neuropsychiatric symptoms (impulsivity, hypomania [14]) resulting from DBS contribute to burden on caregivers [24] who are sometimes deeply troubled by the effects of this therapy [25].

Despite all these good reasons to take the caregiver’s perspective into consideration, the question still remains what weight this perspective should have in the case of conflict with the patient’s perspective. This question merits an ethical evaluation (and a paper) of its own, without which it is difficult to give a straightforward answer. At least the caregiver’s perspective should be considered to evaluate what therapeutic approach could work in practice for that caregiver-patient “constellation”.

Other ethical challenges are related to the necessity to make treatment decisions in light of possible changes in the patient’s cognitive capacity or change in the patient’s values and priorities over time. As device-aided therapies are chosen considering the patient’s personal preferences, and not only clinical indications/contraindications and the patient’s symptom profile, it becomes important to discuss advanced therapies early, well before excessive deterioration of PD symptoms [6], especially nonmotor ones. Bringing up advanced therapies first when they have become acutely necessary may require careful consideration when the patient’s cognitive capacity is already reduced. Advance planning would enable collaboration to identify values, goals, and preferences early and facilitate care concordant with patient’s wishes [26]. But early discussions about advanced therapies have their own challenges –patients may worry that this would reduce the quality of their care or that such conversations indicate that the health professionals expect immediate progression of PD [26]. At this point, reassurance may be needed that such conversations are intended to help patients reflect on both their current goals and values and foreseeable selves in the future early in the disease and should be seen as a dynamic process rather than a one-time event [26]. Early and multiple discussions are also important considering possible changes in patients’ values and priorities over time or difficulties to make hypothetical decisions about future care when the disease has advanced.

SELECTED ETHICAL CHALLENGES IN BRINGING ATMPS TO THE CLINIC

The injured brain has a limited ability to repair itself. Finding ways to restore damaged networks is a challenge for scientists [4]. The main task for ATMP-based therapies is to provide such restoring possibilities. To date, the biggest potential for PD treatment using ATMPs is within stem cell-based therapy [8], distinguished by its potential to replace nerve cells to compensate for those lost in the degenerative process [16, 27]. To date this approach remains experimental and a number of first-in-human clinical trials (CTs) using cells derived from both human embryonic stem cells and induced pluripotent stem cells are on the way [28, 29]. The road to clinical application of certain types of cell-based therapies is estimated to be long, entailing challenges in controlling differentiation into defined subtypes of cells, reducing the immune response that occurs in the central nervous system [16] and assuring that the produced cells are safe (e.g., with reduced risks of tumorigenesis [15]) and efficacious, as well as Good Manufacturing Practice –compliant, which is necessary for their use in patients [28]. Another significant advance is in the area of gene therapy where a single injection of a gene into a nerve cell could give rise to a continuous production of the associated protein [8], which could potentially stimulate dying nerve cells to regrow and thus reverse the progression of PD [8]. Importantly, to enter clinical application, ATMP-based therapies need to hold sufficient competitiveness compared with conventional therapies, both when it comes to their availability and therapeutic effectiveness [15]. Their testing in clinical trials is highly regulated and subject to prospective ethical review, where balance between potential benefit and potential harm is extensively debated, among other things, making sure that potential research subjects can be asked to consider given risks. Ethical challenges in this field are very diverse, relating to informed consent process, methodological issues or diverse application of legal requirements. Here follow some examples.

The particular difficulty in obtaining informed consent for participation in CTs using ATMPs is the high degree of complexity to be communicated to the patient. For a patient without a solid medical or scientific background it can be difficult to grasp how ATMPs are produced and what they do in the body. Likewise, risks associated with ATMPs, especially in interventions using pluripotent stem cells, may be difficult for patients to perceive. Moreover, many cell-based therapies are irreversible, meaning that a patient would become a trial participant for life in the sense that transplanted cells cannot be taken out from the body and would continue to affect the patient even if they withdraw from the study. This may become an exclusion criterion for entering some other clinical trials in the future, thus limiting the patient’s future choices. To be able to choose, one has to understand what the options are. Therefore, participant information should provide all relevant facts about a given trial [30] and a lot of effort should go to increase layperson-adapted understandability of participant information sheets.

Cell or gene therapies for PD are still some years away [31] and experimental. Attitudes toward CTs in general are encouragingly positive among PD patients [32]. Enrolling a sufficient number and appropriately diverse group of patients with PD is important for the success of first-in-human clinical trials [15, 33]. But it is of utmost importance to prevent the therapeutic misconception. One empirical study found that older patients and those with lower education often had inadequate knowledge of the nature and purpose of clinical research in general and were more likely to suffer therapeutic misconception [32], but patients may also become vulnerable for therapeutic misconception due to other factors such as despair.

Prevention of hype is likewise important. For the first, to date there is no scientific evidence that patients suffering from neurodegenerative diseases treated with disease-modifying experimental interventions would have better outcomes than their counterparts in placebo arms. A recent empirical study, examined whether clinical trial participants randomised to unapproved, disease-modifying interventions in neurodegenerative disease, including PD, had better outcomes than those randomised to placebo [34]. It provided evidentiary grounds for clinicians to temper patient expectations in informed consent discussions, but did not rule out benefits from accessing investigational treatments to some individuals [34]. Secondly, unrealistic expectations as to personal health benefits associated with a CT may lead to distrust in CTs among trial participants [32].

Among CT methodology-related ethical challenges is the difficulty to compare the safety and efficacy of studied therapies and to inform patients adequately. To obtain relevant safety and efficacy information scientists need to collect robust and comparable evidence, e.g. in cell therapy, high variability in CTs in terms of donor tissue source, culture conditions, PD stage in which a studied therapy was applied, route of administration, dose, clinical evaluation criteria, and timing of evaluation can lead to inconsistent results [35]. This difficulty to obtain robust knowledge makes it hard to properly design new studies and has a bearing on trial participant safety.

The therapeutic use of ATMPs outside clinical trials, and thus outside research enterprise in the strict sense, under the so-called “hospital exemption” 1, poses another type of ethical challenge. Different interpretation of legal requirements regulating the use of ATMPs as hospital exemption can lead to disparities between countries regarding the implementation of the hospital exemption rule, which raises concerns about patient safety. To illustrate this point, the example of the EU has been chosen (for examples see Table 2).

Besides applying ATMPs outside clinical trials under the “hospital exemption”, controversial uses, such as marketing and provision of unproven cell therapies by “stem cell clinics” have been around for a while and are difficult to regulate internationally. It can be very challenging for patients and their caregivers to navigate among participating in clinical trials and seeking help from clinics selling unproven therapies. These issues are outside the scope of this paper but are so important that they would merit an article of their own.

CONCLUSION

This paper has reviewed different types of ethical issues arising when advanced therapies, device-aided or ATMP-based, are proposed to PD patients either in the form of advanced care, or a clinical trial, or, in case of ATMPs, under the “hospital exemption” rule, using EU legislation as an illustration. The ethical challenges reviewed relate mainly to ensuring informed consent in these different situations, to the role of patient’s familial caretakers as potential source of information about patient’s goals and values, but also as stakeholders affected by treatment choices, and to patient safety in treatments under “hospital exemption”. Common ethical concern across both types of advanced therapies is the need for greater patient involvement in decision-making about their present and future care and facilitating greater understanding of their own goals and motives as well as suggested treatment, either conventional or experimental. This paper does not claim completeness of ethical issues raised by bringing advanced therapies for PD to the clinic, but rather presents examples of common ethical challenges which arise when advanced therapies such as device-aided therapies and ATMPs are applied for treatment of PD.