Team:SDU-Denmark/Ethics
Ethics
Abstract
On this page you can read about our ethics, i.e. how we have evaluated that
our project is ethically permissible. We have mainly done this through an evaluation
of the standard approvement processes for new medication in Denmark and the EU.
Introduction
There are several important ethical considerations to be made when dealing with medication, especially new and controversial kinds. Psychedelic medicine, including psilocybin, is no exception. In our project, we have considered things such as how much focus there might be on psychedelics from the government and the general public, if it is ethically permissible to put GMOs in humans, and of course, if it is a good thing to help make psilocybin more available by trying to reduce its price on the market. These lay the grounds for a few of our discussions; however, after choosing the manufacturing track for our iGEM project, we decided to sharpen our focus on our approach to ethics. To help determine what to focus on, we reached out to a professor in philosophy at our university, namely Søren Harnow Klausen. We talked with him about the considerations we had already made, and he gave us food for thought. Some of the things we integrated into the project from this interview, was defining depression philosophically and focusing on specific ethical aspects instead of trying to do it all.
After talking to Søren, we also contacted The Danish Council on Ethics, consisting of 17 members and working with settling ethical matters regarding technological development – evolvement in the medical profession being no exception.[1] We talked to Martin Ejsing Christensen, cand. mag., Ph.D., who works as a consultant and project manager for The Danish Council on Ethics. He helped us polish our ethical framework. The main point we integrated into our project from this interview was our approach to whether it is ethically permissible to use psychedelics as medicine at all. Of course, this question breeds the question of whether it is good to help make psilocybin more available by trying to reduce its price on the market – which is what we are trying to do in our iGEM project. But Martin pointed out that we were exploring a question that had quite a simple answer. He told us that it is challenging to find solid ethical arguments against our project if the medical procedures are complied with. "There is institutionalized ethics in the procedures that exist", he said. [2] By procedures, Martin was referring to the Danish Medicines Agency and the European Medicine Agency's procedures for approving new medication. So, instead of reinventing the wheel, we decided to look at these procedures and evaluate what sort of ethical considerations they contain.
Approval Procedures
For a medicament to be allowed to be sold in Denmark, it needs to have been approved by either the Danish or the European Medicines Agency. There are four different procedures for this approval:
1. The National Procedure
2. The Central Procedure
3. Decentral Procedure
4. Mutual Recognition Procedure
The national procedure requires the medicament to be approved by just one EU country in order to be approved for marketing in Denmark. The central procedure requires the medicine to be approved in all EU countries at once. The decentral procedure is the procedure where there is sought approval in more than one EU country simultaneously. The mutual recognition procedure is what is used when approval of a medicament in one EU country forms the foundation for approval in another EU country.[3] The application sent to the Danish, or the European Medicines Agency must include documentation for the medicine's effect, quality, and safety. If it is approved, the company that has sent the application will receive permission for marketing the medicament and will then be allowed to sell and distribute it under marketing law.[4] But for this to happen, the documentation included in the application needs to hold solid and scientific proof for the medicine's effect on humans. This proof typically follows clinical experimentation conducted by scientists in the relevant field. It is a rather lengthy procedure, and it can take many years from the first experiments to attaining solid documentation.
The different phases of clinical experimentation
Firstly in vitro experiments are performed with the medicament. This means that the experiment is executed on a cell line in a petri dish (often of human origin). These experiments aim to determine the biochemical mechanism of the drug within the specific cell type. This phase can take multiple years. The limitation with in vitro studies is the lack of communication between the different cells responding to the drug. Therefore, the drug needs to be tested on a multicellular organism, similar to humans. After that, if approved, the drug can be tested in vivo, which means on an entire organism. Here mice are often used but may vary depending on the mechanism of the drug. The experimental setup should firstly be approved by the committee of animal ethics of the corresponding country. These studies aim to assess the effect, mechanism, and risk associated with the drug. The drug's entire pathway through the organism should also be investigated, which is absorption, distribution within the body, how it is metabolized and excreted from the body. This phase often also often takes multiple years.
For the drug to be approved in Denmark, the drug's effect in both experimental designs must be investigated for approval by the Danish Medicines Agency, the scientific committee, and the data inspectorate. If approved, the first phase of the clinical trials begins with a relatively small experimental group. This experiment is often tested one patient at a time, to reduce the risk that may be associated with the drug. In phase two, a larger group of the drug's target group is treated with the drug. Both safety and the effective dose are investigated within phase two. In phase three, the drug is tested on a larger group of patients under more realistic conditions. Phase four can begin after the approval for the marketing of the drug. This phase aims to investigate the optimization of the treatment as well as if different medications may affect the investigated drug's effect. [5]
If a medicament has undergone the entire process of clinical experimentation and there has been attained sufficient documentation for the medicine's effect and its quality from large-scale scientific trials, only then will the Danish or the European Medicines Agency approve it to be distributed to the public. [6] Of course, a lot of medicine is never directly distributed to the general public. It is instead handled and prescribed by medical professionals.
Evaluation
Now that we have gone through the official procedures and their contents, we can take a closer, and perhaps critical, look at what sort of philosophical and ethical considerations they contain. We will also evaluate their ethical values from a theoretical perspective.
Phases in Clinical Experimentation
Phase 1: In vitro
Firstly, the in vitro experiments. This very first phase is cells that are tested in a petri dish. Even though there will be philosophers who will take on the discussion about the ethics of micro-life and cells, this is a minor one and not one we will pursue here. However, a few things can be said about it briefly. Looking at this phase from a theoretical perspective, two main ethical approaches to consider are consequentialism and deontology, also known as utilitarianism, and ethics of duty.
Consequentialism, as its name suggests, is simply the view
that normative properties depend only on consequences. [7]
The conclusion from a consequentialist on this phase one in vitro experiments would be straightforward. Considering how many people have, and will benefit from modern medicine, the possible (minor) consequences of using human cells are insignificant. So, in a consequential framework, the conclusion is that there are no ethical issues in phase one of clinical experimentation. From a theoretical standpoint, deontology is the opposition to consequentialism. However, with this first phase, it seems that the consequentialist and the deontologist would agree.
In contemporary moral philosophy, deontology is one of
those kinds of normative theories regarding which choices
are morally required, forbidden, or permitted. In other words,
deontology falls within the domain of moral theories that guide
and assess our choices of what we ought to do. [8]
The deontologist is rule-guided, which means that the right choice from a deontological perspective is the one that follows a set of rules. Clinical experimentation follows the rules. Thus, the deontologist would not have any qualms about in vitro experiments, as they can be conducted in scientific matters. To sum up this evaluation, phase one of clinical experimentation seems to be ethically permissible from the theoretical framework of consequentialism and deontology.
Phase 2: In vivo
Phase two, which is the in vivo drug experiments, is a somewhat controversial kind. This is the phase of clinical experimentation where animals are used, often mice. We will focus on a few specific aspects of the discussion on ethics in animal experimentation.
We will start by introducing the European Medicines Agency's (EMA) approach to animal ethics and afterwards present a counterargument from Peter Singer for the use of animals in medicine testing. EMA's website has included a page about the ethical use of animals in medicine testing. They start it off with:
The European Medicines Agency (EMA) supports the implementation
of the so-called 3Rs principles - replace, reduce and refine - for the
ethical use of animals in medicine testing across the European Union (EU).
These principles encourage alternatives to the use of animals in the testing of
medicines while safeguarding scientific quality and improving animal welfare
where the use of animals cannot be avoided." [9]
The EMA has here concluded that by implementing these 3R principles, they are, per definition, using animals ethically. But are they? We will take a closer look at the 3R principles.
More specifically, the 3R´s stand for:
• replacing the use of animals with non-animal methods where possible;
• reducing the number of animals used to a minimum while still obtaining scientifically valid results;
• refining practices to minimize the stress and improve the welfare of study animals used for regulatory purposes. [9]
Shallow analysis of the 3R based on the theoretical framework of consequentialism and deontology is that they are (by default) ethically permissible. However, instead of going deeper into the arguments that can be made from these ethical branches, we will turn to Peter Singer. He is a world-famous professor of bioethics, who, amongst other things, has written the famous book Animal Liberation which was published in 1975. [10] In this book, Peter Singer makes a case for the end of our exploitation of animals in all industries, based on a line of arguments against speciesism.
Speciesism is the unjustified disadvantageous consideration
or treatment of those who are not classified as belonging
to one or more particular species. [11]
The argument for speciesism is based on the premise that humans are worth more than animals. But Singer believes that this is merely a prejudice argument. He rejects it based on two counterarguments. Peter Singers' first argument against speciesism is about cognitive ability. In short, Singer says that we cannot discriminate against animals because of their inferior cognitive skills. This conclusion rests on the ground that there are animals whose cognitive abilities are superior to some humans. Singer's example of this is mentally retarded human beings, who rank lower than certain animals in a range of parameters. These are parameters such as IQ, supervision, speech ability, and social isolation.[12] So, Singer's point with this argument is simply to show that we cannot discriminate against animals due to their lack of cognitive abilities. Doing so implies that humans with cognitive limitations do not have the same status as people with normal cognitive functioning. Peter Singers' second counterargument targets religious reasoning. Some speciesists believe that humans are superior to animals because God created us and gave us dominion over animals. But as an atheist Singer labels this argument as false and adds that even if it were true, it shouldn't count in a secular society. Based on these two arguments, Singer says that we should reject speciesism and treat animals as equals, thus not exploiting them.[12]
This also means that we should not use them as testing objects in science. Peter Singer elaborates on this aspect of animal ethics in chapter two of his book Animal Liberation. [13] But summing this ethical review of phase two of clinical experimentation up, we have briefly described that it is ethically permissible to use animals in medicine testing at least consequentially and probably also deontologically. However, several counterarguments can be made in this regard. We introduced two of them here, both of which come from the philosopher Peter Singer. The EMA believes that its procedures ensure the ethical use of animals in medicine. Philosophically speaking, though, it remains yet to be determined whether this exists.
Phase 3 and 4: Clinical Trials
The final two phases of clinical experimentation are clinical trials that involve humans. There are some considerations to be made here as well. First, any clinical trials need approval. In Denmark, it is the Danish Medicines Agency that´s responsible for approving clinical trials. According to §88 in the law about medicaments, one must apply for authorization to complete trials. [3] Once permission is gained, the trial can be conducted. However, there are several guidelines in place for good clinical practice that need to be followed during the trial. [6] The EMA´s Committee for Human Medicinal Products has developed a full report with Guidelines for good clinical practice. The first principle of these guidelines is:
Clinical trials should be conducted in accordance with the ethical
principles that have their origin in the Declaration of Helsinki, and
that are consistent with GCP and the applicable regulatory requirement(s). [14]
So, the EMA refers to the ethical principles from the Declaration of Helsinki as the ethical standard that clinical trials must meet. But what is this Declaration? It is an agreement first conducted in 1964 and revised about eight times since. [15] It is formulated by the World Medical Association, and the latest edition consists of 37 principles. You can read all 37 principles here. The principles are divided into 12 categories in the Declaration, whereas one is about research ethics committees and entails principle 23.
The research protocol must be submitted for consideration, comment,
guidance, and approval to the concerned research ethics committee before the study begins. [16]
These are the first two lines of principle 23. In this excerpt of the principle, it seems clear that the Declaration of Helsinki calls for independent ethics committees to evaluate each clinical trial before perpetration. This is consistent with part 3 of the EMA´s guideline for good clinical practices.
An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects.
Special attention should be paid to trials that may include vulnerable subjects. [14]
IRB stands for Institutional Review Board, and IEC stands for Independent Ethics Committee. Essentially the EMA refers to the Declaration of Helsinki´s ethical principles, which refer to ethics committees in the same way that the EMA does later in their report. It seems to be a bit of a circular argument. However, the Declaration of Helsinki does have 36 other ethical principles. They concern considerations about risks, vulnerable patients, scientific requirements, informed consent, placebo, and more. These are normative principles, and they do seem to be very generic, i.e., lack more specific guidance. Perhaps this is the purpose of the concerned research ethics committee. That is, to specify and evaluate domains particular to the clinical trial in question. In sum, phase 3 and 4 follow the Declaration of Helsinki, which states that an independent ethics committee must be appointed for all clinical trials. This seems like a plausible way to make sure that trials keep within what is considered to be ethically permissible.
So, the EMA´s guidelines for good clinical practice seem sufficient, at least specifically regarding the ethics concerning clinical trials. An independent ethics committee holds the resources and competencies to evaluate the ethics of each clinical trial in depth. At least we assume so. They are thus more capable of evaluating the cost/benefits of each trial, hence deciding if the trial is good for the world. In conclusion, this means that the EMA´s guidelines for good clinical practice are sufficient to ensure good clinical practice to be complied with.
Ethics in the EU´s Approval Procedures
Now let's talk about the four kinds of approval procedures in the EU: the national, central, decentral, and mutual recognition procedures. As you might remember, the national procedure is where a medicament needs only to have been approved in one other EU country to be marketed in Denmark. To this procedure, one might ask if it is sufficient to rely on one other country's approval of a medicament. It might be that the country in question has a whole other set of values and that their approval procedures reflect this. Or perhaps they have a different approach to treating mental and physical illnesses. It need not be an inferior approach necessarily, but in such as case, it would at least be necessary to investigate how this other country's procedures differ from others. If this investigation took place before simply approving the medicine based on someone else's evaluation, the national procedure might be sufficient. However, it seems that the central and decentral procedures are more reliable if we talk about them from an epistemological perspective. At least if we accept the premise that collective wisdom does exist. This is widely discussed within the epistemological domain, with no simple answer to what is right. [17] The fourth procedure, i.e., the mutual recognition procedure, faces the same challenges as the national procedure: sufficiency and reliance on another country's approval procedures. However, this procedure seems to have an important component that the national procedure does not. With the mutual recognition procedure, a medicament is not simply approved in one country because it has already been in another. Instead, the mutual recognition procedure uses the approval of a drug from other countries as a foundation for further investigation. This means that the medicament in question will not immediately be approved simply because another EU country has approved it. Instead, it will form the foundation for approval. It seems that this approach to approving new medicine might be a more thorough one.
Summary
As a part of establishing whether our iGEM project was, in fact, responsible and good for the world, we decided to investigate what ethical considerations we needed to take. First, we asked ourselves whether it was ethically permissible to contribute to making psilocybin cheaper (and thereby more available). Then we talked to Søren Harnow Klausen and the ethical board to fine-adjust our ethical framework. These interviews got us to look at our ethics differently. We then decided to investigate the ethical aspects of the procedures that psilocybin must go through to be approved as a medicament. The procedures we chose to look at originates respectively from the Danish and European Medicines Agencies. We chose these as they are the processes psilocybin must go through to be approved for medical use in Denmark.
We started by going through the procedures to gain an understanding of how they are structured. Then we took a closer look at what ethical considerations they entail. We learned that they have ethics integrated into them—not strictly formulated as to what is ethically permissible and what is not, but with requirements of involvement of ethical boards in each specific case. From this, we conclude that the EMA procedures are sufficient from our point of view. Furthermore, this means that we do not need to consider whether it is ethically permissible to make psilocybin cheaper. This is because if our iGEM project succeeds beyond the competition itself, and we contribute to lowering the price of psilocybin on the market, then it is not our concern what happens afterward. This burden lies on the shoulders of the ethical boards involved in approving psilocybin as a medicament. Hence, we conclude that PsiloAid is a responsible project from an ethical point of view.
References
[2] Interview with M.E. Christensen. 2021. Interviewer N. Dimple.
[3] Approval Procedures [Internet]. Danish Medicines Agency. 2020 [cited 20 October 2021]. Available from: https://laegemiddelstyrelsen.dk/da/godkendelse /godkendelsesprocedurer/
[4] Approval of medicine [Internet]. Lægemiddelstyrelsen. 2020 [cited 20 October 2021]. Available from: https://laegemiddelstyrelsen.dk/da/godkendelse /godkendelse-af-medicin/
[5] Phases for clinical experiments [Internet]. Lægemiddelstyrelsen. 2019 [cited 20 October 2021]. Available from: https://laegemiddelstyrelsen.dk/da/godkendelse/kliniske-forsoeg/hvad-er-et-klinisk-forsoeg/faser-i-kliniske-forsoeg/
[6] Guide for applying for permission for clinical trials [Internet]. Danish Medicines Agency. 2020 [cited 20 October 2021]. Available from: https://laegemiddelstyrelsen.dk/da/godkendelse/kliniske-forsoeg/ansoegning-om-kliniske-laegemiddelforsoeg-med-mennesker/ansoegning-om-nye-kliniske-laegemiddelforsoeg/#LOVGIVNING
[7] Consequentialism (Stanford Encyclopedia of Philosophy) [Internet]. Plato.stanford.edu. 2020 [cited 20 October 2021]. Available from: https://plato.stanford.edu/entries/consequentialism/?utm_campaign=Matt%27s%20Thoughts%20In%20 Between&utm_medium=email&utm_source= Revue%20newsletter
[8] Alexander L, Moore M. Deontological Ethics (Stanford Encyclopedia of Philosophy) [Internet]. Plato.stanford.edu. 2021 [cited 20 October 2021]. Available from: https://plato.stanford.edu/entries/ethics-deontological/
[9] Ethical use of animals in medicine testing - European Medicines Agency [Internet]. European Medicines Agency. 2021 [cited 20 October 2021]. Available from: https://www.ema.europa.eu/en/human-regulatory/research-development/ethical-use-animals-medicine-testing
[10] Peter Singer [Internet]. Peter Singer. 2021 [cited 20 October 2021]. Available from: https://petersinger.info/
[11] Horta O. What is Speciesism?. Journal of Agricultural and Environmental Ethics. 2010;23(3):1-31.
[12] Singer P. Speciesism and moral status. Metaphilosophy. 2009;40(3-4):567-581.
[13] Singer, P. (2009). Animal Liberation. Harper Perennial.
[14] European Medicines Agency consults on guidelines for first-in-human clinical trials. The Pharmaceutical Journal. 2016;.
[15] WMA - The World Medical Association-WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Subjects [Internet]. Wma.net. 2018 [cited 20 October 2021]. Available from: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/
[16] World Medical Association Declaration of Helsinki. JAMA. 2013;310(20):2191.
[17] For further reading on the subject, we recommend "What to Believe Now" by David Coady
Defining depression
