Designing clinical trials for future space missions as a pathway to changing how clinical trials are conducted on Earth

The project aims to build a framework for conducting clinical trials for long‐term interplanetary missions to contribute to innovation in clinical trials on Earth, especially around patient involvement and ownership.

medicine, the number of astronauts is limited so commissioning large clinical trials is challenging, resulting in either small case studies or simulating space conditions on Earth to provide additional numbers and facilitate randomization. Additionally, due to the environment and lack of gravity, there will be new questions when randomization to the control group is detrimental to health and consequently unethical.
Future research for space exploration will not only require repeating terrestrial research in simulated/space environments, it also requires innovative approaches to the methods of clinical research to investigate these new challenges. Long-term missions require the continuous commitment and motivation of participants in the clinical trial; therefore patient involvement in the research process is more important. In this project, we developed and piloted a new approachspeculative theorization using simulation (including virtual reality [VR] and live-simulation) grounded in evidence synthesis. The project used speculative theorization to identify new methods to study complex applied clinical research questions and engage with a more diverse group of individuals from different disciplines and experiences. This pilot focused on a specific research topic-conducting clinical trials for the health of astronauts in micro, or partial, gravity. As the project developed, we realized the speculative theorization is also a beneficial thought experiment to encourage trialists, practitioners and members of the public to think more seriously about how to design inclusive clinical trials in partnerships about patients due to the restrictive nature of the scenario-you have to design the trial in a way that all or at least more participants agree to participate and also consider the social and cultural implications of the trial on the community.
The project started a few systematic reviews 1-3 around specific questions in aerospace medicine that highlighted some issues around systematic reviews and primary studies in aerospace medicine.
The methods to synthesize evidence on a focused health research question are well documented in the literature. 4,5 However, there are specific challenges in reviews of aerospace medicine that we observed in previous reviews, 1,2 like databases and resources to search for studies ( Table 1). The other issues are highlighted in Table 2. Systematic reviews will use certain structure likes PICO (stands for participants/population, intervention, comparison, outcome) to focus the research question. In the case of systematic reviews in aerospace medicine, the population are usually either astronauts, space tourists or individuals participating in simulated studies attempting to replicate a certain aspect of space missions. In the previous reviews that we were involved, the outcome measurements that were predominately used in the included studies (and to our knowledge in a lot of space operations) are biomedical or physiological outcomes. We raised the need to include patient-relevant outcomes in these trials, and it was also a topic that came up in this project.
These issues might be a reflection of the culture of medicine in space is predominantly top-down, that is, astronauts are required to do all manner of medical tests and have them performed on themselves in order to be astronauts. The Mars scenario fundamentally challenges the space industry culture of medical tests. However, this proposed culture-shift to an all-inclusive test paradigm for crews also begs questions of the culture of medical trials as they are on Earth and the capacity to change the existing structures and frameworks.
At this stage, it is also worth mentioning a current recent incidence related to the communication between an astronaut and his clinician.

Chris Hadfield talks in his book about how a panel of surgeons decided
on surgery for him without consulting him before his last mission to International Space Station. He resisted the decision as there was inadequate evidence to support it. This example demonstrates the different values and preferences of the person involved and the managers in situations when the evidence is uncertain. 6 This study uses a methodological approach that shares traits with speculative and critical design, using imagined scenarios, props, imagery, and diegetic prototypes to raise questions regarding preferable futures. These design methods often take inspiration from science/speculative fiction as a way to trigger debate and discussion. 7 The influence of art and culture (including futuristic media) may shape or influence our vision of the future and even guide the design of medical products, but currently there are few visions of future medical research that encompasses innovation of methods of clinical research.
To build the scenario for this workshop that is both future-facing as well as retaining and drawing from present medical knowledge, the experience and questions contained tropes from both science fiction as well as tropes from the history of clinical trials. An example that influenced the scenario built for this workshop is that of sailors affected by scurvy on naval vessels in the 17th century, a situation that shares resemblances to the conundrum of clinical trials in space missions. 8 Popular science fiction movies can shape or influence our imagination for the future but do not engage all aspects of medical research development. For example, the Qualcomm Tricorder X-prize has been awarded to a family-led team to develop a medical device that intended to develop technologies to diagnose a set of 13 medical conditions independent of health professionals or facilities and continuously measure five vital signs in 2017. The idea was inspired by the popular science fiction series Star Trek. In the Star Trek series and similar sci-fi movies and series, a doctor uses complex technologies to make very accurate diagnoses (through micro-and nanotechnologies, data and information) and often finds a treatment to cure the problem/disease (in lots of cases to total health without adverse events). In this and similar popular sci-fi movies and series, the storyline emphasizes the  It has similar gaps to the previous one. In addition to this, the issue of finding the threshold for gravity that has the least problematic impact on the human body which requires regression analysis and exposure of different types of gravities.
In relation to this project, we can translate the issue of changes in gravity on the human body to get to Mars; from earth gravity to microgravity and then the partial gravity on Mars.
different implications in space that can affect the decision-making process.

METHODS
We designed a creative workshop that included a simulation of a disaster during a space mission, the usage of optical design to distort vision and an interactive methodological discussion. The workshop was based on the topics identified from previous systematic reviews (Table 2) and the speculative theorization around clinical trials in space missions. It intended to create altered states such as a different weight and different perspective to jolt participants into imagining the realities of astronauts.
The workshop was shaped around a speculative scenario ( Table 3).

RESULTS
The issues and concepts identified as part of the workshops can be cat-

Item Explanation
Case scenario In a mission to Mars, there are 40-50 people who are staying on that planet for three years. You have increasing reports of individuals having differing eye problems, eg, blurriness, seeing spots, problems in seeing distance, etc. These eye problems are affecting the ability of individuals to perform their duties and affecting the mission in general. Moreover, it causes anxiety and stress as other members of the mission are worried that they might become affected. You need to come up with a solution to manage the situation and determine how to conduct clinical research that not only supports this mission but future ones. Note: The scenario is based on recent reports that some astronauts experience vision impairment that can last for a long time during and after space missions. The participants received quotes from astronauts that was available in publicly available documents, eg, a quote from astronaut Mike Baratt-"It's my right eye that has apparently been permanently remodeled."

Approaches to be inclusive in the management of the trial
Astronauts have a lot of experience in conducting experiments as part of a daily routine in space missions, so we expect that being part of a clinical trial will be easier for them than standard patients. However, we do not know how human behavior changes or adapts on long-term missions and we expect that it will be more difficult-the isolation and

Approaches to be inclusive in designing the research project
One of the biggest challenges of aerospace medicine research is the low sample size as the number of astronauts is limited. This, unfortunately, is also often the case with simulation studies. Due to the technical requirements and costs, the number of individuals that can be recruited in space mission clinical trials is limited. Systematic reviews with meta-analyses have been used to synthesize the data across clinical trials, and these can increase the power and generalizability of results. There is a possibility to address this issue using prospective meta-analysis, which requires the space agencies to plan the clinical trials, keeping in mind the future meta-analysis in which the clinical trial will be included. In this way, they could also plan those clinical trials over several space missions, especially as a health issue will probably come up repeatedly in future missions with new individuals. 10 During the discussion around the speculative scenario, the question was raised whether this scenario challenges the notion that the standard RCT is the most appropriate methodology. The ethical challenges might favor alternatives such as N-of-1 or a stepped wedge. Regarding the aforementioned eye problem, in some cases, we might not be able to treat the problem and might need to find ways to ensure that the individuals manage symptoms to be able to perform their duties or live their lives. In these cases and these types of treatment, N-of-1 trials can be useful, so will be helpful if individuals have access to ways to incorporate these trials in their daily life. 11 Given the small number of participants, difficulty to maintain equipoise and the ethics of the same population being involved, participants might favor an alternative. However, this issue was not raised in any of our workshops. In future workshops, we will explore whether the latter is a consequence of how the workshop was structured or the issue may not be considered relevant by the participants attending our workshop.
In both workshops, people raised the issue that not only would clinical and biomedical outcomes need to be collected, but also patientrelated outcomes and performance-related ones (what people care about). There was also a discussion on unexpected outcomes, for example, unexpected side effects and the need to record and identify them.
Some even suggested that we would collect data on each member's log (which does raise ethical and consent issues).
During the workshops, people raised concerns about a set of predefined and fixed outcomes at the beginning of the clinical trial. This is important to provide relevant comparison; however, people's priorities on what the most important outcomes are might change over time.
Therefore, it has been suggested that the clinical trial team should have a continuous discussion with individuals in the group to see how the outcomes evolve.

Balancing the research needs and the community needs
Clinical trials usually involve randomization in different treatment groups. We sometimes stratify individuals in the groups based on other confounders to explore their impact on the effectiveness of the intervention. During the workshops, the issue was raised that each person has a critical role in the mission. It's vital that if the performance of the individual is negatively affected by the trial (either that the intervention does not work or the intervention has side effects), that people with similar roles and job specification would not be in the same treatment group. Another reason for not having people with similar roles or similar living or working places to be in the same group is the possibility of contamination between groups. In these situations, one could implement stratified randomization to separate them by allocating them to groups. Moreover, the investigator could use weighted/unequal randomization which is still randomized but results in fewer participants allocated to the experimental group (or nonexperimental group whichever is deemed to have adverse consequences) (adaptive design). 11,12 There are alternative methods for designing the clinical trial which can be used, such as patient-preferred clinical trials, or different approaches to randomizing people to the groups, such as adaptive design clinical trials.

Ethics and partnerships
The importance of partnerships and transparency was raised. The current global pandemic outbreak of coronavirus raises questions, not only about how we manage the situation, but also about how we develop an infrastructure to collect data in a more systematic way to inform future decision making. Currently, many countries have chosen social distancing as an intervention to reduce the speed of the spread of the infection. However, good quality data will be key to understanding whether the long term benefits of the intervention outweigh its social and economic consequences. This project can be used to train individuals to find new processes and methods for unprecedented situations, such as disasters and pandemics.

CONCLUSION
This methodology provides a useful approach to re-think the research Speculative theorization using simulation and visualization grounded in evidence synthesis can be used for other methodological questions in aerospace medicine and wider health care research.
For this specific topic, we intend to conduct additional workshops focusing on certain aspects of a clinical trial with a more diverse range of scenarios that include other types of health problems, for example, contagious ones or datasets that reflect the issues identified in this exercise.

ACKNOWLEDGMENTS
We would like to thank Eleanor Gonzaga, Klara Lucznic, Andrew Pugsley, Daniel Rose, Hans Lund, Klara Brunnhuber, Jennifer Yost for their input and contributions to developing the concept, material or commenting on the manuscript and we would like to thank Julian Wright, Daniel Rose and the rest of the VR team at Torbay Hospital for their amazing work and visualizations. We would also like to thank Terry Pope for providing the hyperscope and pseusoscope.