Conference organized by the Nordic Committee on Bioethics in collaboration with Centre for Legal Studies in Welfare and Market at the University of Copenhagen.
Venue: Alf Ross auditorium (room 9A-3-01), Faculty of Law, University of Copenhagen

Session 1 - How are clinical innovations/unproven methods developed and introduced?

"Ethics and Policy Surrounding Patient Access to Experimental Therapy",
Professor Jonathan Kimmelman, Director of Biomedical Ethics Unit, McGill
Debates about patient access to experimental interventions are often framed as a zero sum gain between private preferences of patients and public interest, or between innovation and patient protection. After describing existing and proposed regulatory mechanisms for facilitating patients access to experimental interventions, I will offer several reasons why the above framings are inapt, and why oversight systems should restrict access to experimental interventions. First, early in drug development, researchers rarely know how to use an intervention, much less whether it is safe and effective. Second, evidence suggests that patients do not benefit by accessing unproven interventions; if anything they are more often harmed. Third, the evidence standing behind novel interventions is often surprisingly weak.  Last, liberalizing patient access to experimental interventions can have damaging effects on meaningful biomedical innovation. After considering some rejoinders to my argument, I close by suggesting that debates about access are best understood not in terms of private vs. public gain, but rather in terms of who should bear the burdens and costs of medical uncertainty. I suggest that any system committed to equitable distribution of such burdens ought to be very restrictive about liberalizing access to experimental interventions.

“Experimental oncolytic immunotherapy for individualized treatment of cancer patients incurable with routine approaches ”, Professor Akseli Hemminki, University of Helsinki
Oncolytic viruses have been used for treatment of cancer for more than a century, but the finding that a major part of their anti-tumor activity is due to activation of the immune system, is a relatively recent one. Thus, currently these agents are viewed more as immunotherapy than sterile oncolytic drugs. Key to this realization was experience from human cancer patients, since laboratory models often lack the key immunological components. The central findings from our Advanced Therapy Access Program (ATAP), ongoing between 2007-2012, will be explained. 290 cancer patients were treated in an individual manner under the EU Advanced Therapy directive and its Hospital Exemption (Hemminki A, Crossing the Valley of Death with Advanced Cancer Therapy, Nomerta publishing 2015). While robust single agent activity is seen only in a minority of patients with most oncolytic viruses currently in development, they are emerging as key ingredients of combination immunotherapy. Checkpoint inhibitors have gained much attention, due to their ability to achieve lasting responses in immunologically “hot” tumors. However, they do not work in “cold” tumors. Oncolytic viruses are able to turn cold tumors hot, suggesting an attractive combination with some promisining early clinical data.

“ Developing a cancer vaccine, and challenges in performing clinical trials of experimental therapies”, Professor Steinar Aamdal, University of Oslo
UV1 is a novel Therapeutic Cancer Vaccine (TCV) for activation of T-cells against cancer cells and cancer stem cells.
UV1 is developed by comparing immune responses from short term survivors with long term (10 years) survivors of several cancer types. UV1 activates T-cells to mimic the immune responses of long term survivors with broad immune responses against telomerase.
Phase I/IIa clinical trials in androgen sensitive metastatic prostate cancer and non small cell lung cancer respectively showed excellent safety profile and demonstrated ability to induce specific immune responses in a large fraction of the patienst. In a small Phase I trial with UV1 in combination with ipilimumab in melanoma it was shown that the combination was well tolerated and gave rapid immunresponses in more than 90 % of the patients. Currently a Phase I trial with UV1 in combination with pembrolizumab in melanoma patients is ongoing in the US.

“We can do better - a patient perspective”, Anne Sofie Boldsen Salicath, MD, patient representative.
To be diagnosed with stage 4 cancer was by far the most scary thing that has ever happened to me. The second, was to find out the lack of ambition and flexibility that characterize the standard treatments offered to stage 4 patients today. To see the healthcare system settle with safe standard treatments though they have been proven to have only weak results. By repeating what has been shown decades ago, not to work to improve overall survival significantly. Similarly it has been overwhelming to see the interesting scientific evidence potentially available for treatments, at or below phase 3 level, that never reach patients due to for instance, technicalities, lack of ambition and a rigid health care system. And to find out that the fate of the stage 4 patients is literally in their own hands, because the healthcare systems have given up on them.

My talk argues we need to be more ambitious, bold and maybe just getting rid of the box, instead of trying to think outside it. It's about the right to try, because to me, the alternative would be unethical.

Session 2 - What is the legal and regulatory environment concerning clinical innovations in medicine?

"The room for clinical innovation under Swedish law ", Senior Lecturer Lena Wahlberg, Lund University
In this talk, I will give an introduction to the Swedish regulatory framework pertaining to the use of unproven methods in medicine. Specifically, I will address the room for clinical innovation in relation to the fundamental requirement that healthcare workers shall deliver care in accordance with “science and proven experience”. I will also briefly comment on the ethical dimensions of this requirement.

“The regulatory challenges in regards to clinical innovation”, Professor Mette Hartlev, University of Copenhagen
Development of new and better products and methods in health care is generally welcomed by both patients, health care professionals, and society. Consequently, there is a common interest among these actors and innovators in clinical innovation. However, innovation always implies a certain degree of uncertainty regarding benefits and risks – and this is particularly true in regards to radical innovation. Consequently, development and testing of new drugs, technologies and methods in health care takes place in a landscape of uncertainties, which calls for regulatory considerations. This paper explores the role of regulation in regards to clinical innovation. It explores whether (and how) regulators can stimulate and promote innovations to the benefit of society, while at the same time mitigating the potential risks affiliated with clinical innovation. It also discusses the regulatory challenges facing regulators when dealing with new technologies which does not fit into the existing legal and ethical regulatory regime. Consequently, innovation also calls for innovative regulation.

"Regulating Risk in Surgical Innovation? A UK perspective", Dr. Jonathan Ives, University of Bristol
This talk focusses specifically on ethical and legal issues associated with regulating surgical innovation. It will use, as a case study, a recent high profile UK case (2018), where a 69 year old man died following complications during robotic assisted heart surgery. A brief overview of the case will be used to highlight three key problematic areas (1) defining innovation in surgery, (2) consenting for unknown risk and (3) the learning curve, all of which highlight particular challenges for would-be regulators of innovative surgical practice . The talk will conclude by proposing an eliminativist approach to thinking about surgical innovation, and asking whether a regulatory approach that focusses on risk profiles could have prevented this tragic case  

Session 3 - What ethical principles should guide work on emerging treatments and experimentation in hospitals?

"Novel medical treatments, innovation, hope and headlines", Catherine Joynson, Nuffield Council on Bioethics
There is a spectrum of treatments that might be considered to be experimental, from those which have never been used in humans, to those which are used routinely but are not licensed for the condition in question. Experimental treatments include medicines, surgery, medical devices and implants, stem cell and gene therapies, and fertility treatments. There are several ways in which experimental treatments can be supplied and offered to patients within the UK legal and regulatory framework, and crowdfunding has emerged as a way to raise funds for costly medical treatments. The Nuffield Council on Bioethics has identified some of the ethical issues that the use of experimental treatments can raise. These include: difficulties in assessing efficacy and safety; ensuring fairness of access; challenges around decision making and consent in the context of online information; potential impacts on knowledge generation; and ensuring healthcare professionals act responsibly. These challenges can be particularly acute when parents or guardians seek to access experimental treatment for a child or person who lacks capacity to consent. A core challenge is balancing the interests of patients in accessing experimental treatments and the need to support innovation, with ensuring there are sufficient safeguards to protect patients from potential harm(s).

"Harms and benefits in clinical innovation", Dr. Gardar Arnason, University of Tübingen
The use of unproven methods in clinical practice, when proven methods have been exhausted, is variously seen as either a matter of clinical practice, a matter of both research and clinical practice, or as being only defensible when provided in the context of clinical research. First, I discuss the distinction between research and clinical practice and to what extent it matters morally. I then consider the view that the use of unproven methods outside of clinical trials is not research and that the dominating moral principles in this context are respect for autonomy (of both patient and clinician) and clinical freedom. Against this view, I argue that even if clinical innovation is not research, it should be similarly regulated, and, in particular where the unproven method is invasive or poses significant burden or risk to the patient, its use must be reviewed by a research ethics committee or a similar independent, institutional body. I conclude with some thoughts on the importance of producing regulation that not only aims to protect patients while promoting innovation, but that is also robustly implemented and that provides careful and trustworthy oversight mechanisms.

"Ethical principles in unproven methods – is there a need for regulations?", Professor Ingemar Engström, Örebro University/NCBio
In this talk, two Swedish documents on ethical aspects on unproven methods (clinical innovation) are presented. Fundamental ethical principles that have to be taken into account if such methods are to be used in clinical medicine will be discussed. The reports look at ethical value conflicts that can arise when unproven methods are used in health care. Both reports conclude that it is ethically acceptable to provide unproven methods outside research projects under some strictly defined preconditions. In Sweden, this area is not satisfactorily legally regulated. A better regulation should therefore be prioritized.