M a n u s c r i p t Manuscript Doi: 10 .1093/ecco-jcc/jjaa127 Text The COVID-19 pandemic puts enormous pressure on healthcare, especially when it comes to those individuals already suffering from chronic diseases. While it appears that COVID-19 related morbidity and mortality is mainly affecting older adults with pre-existing cardiovascular, metabolic or respiratory co-morbidities, it is apparent that the pediatric, adolescent and adult populations are at risk, too, although with lower incidence rates. Little is known about the role of chronic inflammatory diseases including inflammatory bowel disease (IBD) as a co-morbid risk factor to COVID-19. In the general population, IBD affects children, adults and the elderly with two typical age peaks of onset in early adulthood and around 50 to 60 years of age (1) . At the current time, there are only anecdotal reports of COVID-19 in patients with pre-existing IBD. International registries are now collecting cases in which COVID-19 has developed in the setting of IBD (2) .
IBD represents an entity with a large unmet need for more effective therapies. An estimated 2.000.000 individuals in Europe and 3.500.000 people in North America suffer from the two main entities, Crohn's disease and ulcerative colitis (3) . Even the most effective medical interventions deliver much less than 30% efficacy in terms of induction and maintenance of symptomatic and endoscopic remission (4) . When it comes to more stringent endpoints including control of inflammation markers and histologic healing treatment, efficacy rates are even less (5) . Modern therapeutic options for IBD have been developed at considerable costs for research and development, costs which have been passed on to consumers and payers as among the most expensive therapies available for chronic diseases. The high costs are justified by the large impact of IBD on quality of life and social functions. Affecting more than 10 million people worldwide, the overall value of this therapeutic indication totals to more than EUR 30 billion (USD 32.4 billion) in 2019.
The combination of unmet needs and opportunity for profit has resulted in IBD becoming a competitive battleground for scores of new pharmaceutical developments competing for a potential step innovation in efficacy. Because of this competition, it has become extraordinarily difficult to recruit sufficient numbers of patients into clinical development programs, with recruitment rates as low as 0.1 patient/site/month (6) . The other major challenge for recruitment into IBD clinical trials has been ongoing use of placebo arms, such that patients refuse participation in the trial for fear of being randomized to placebo, which they perceive as inferior or even harmful. To address these This is unfortunately in line with major institutions shedding regular care for the chronically ill and the elderly by concentrating the resources for the care of incoming COVID19 patients which are expected in high numbers. At many medical centers, the clinical trial staff even have been instructed to work from home or take paid leave until the pandemic passes.
The shutdown of elective care by healthcare providers adds an important second aspect, in which the discontinuation of "elective" medical care by health care providers and the denial of clinical trial support by sponsors amplify the effects of one another. However, it is difficult to quantify the actual collateral damage that may have been caused by reduction of non-COVID-19-related healthcare services. Using other chronic diseases as an indicator (e.g. chronic heart, vascular and metabolic diseases), it may be suspected that reduction of elective procedures and access problems to non-COVID related healthcare services may result in a disproportional death rate. However, the result of the epidemiologic perspective is inconclusive and highly dependent on regional jurisdictions. While overall excess mortality rates in Lombardy/Italy (in comparison with expected deaths inferred from the previous years) between March 20 and April 20 were highly increased with a significant proportion of excess death caused by non-COVID-19 indications, (7) in Germany no clear signal of an excess mortality has been seen in the demographic statistics (8) (Fig.1A) . This is in significant contrast to an excess death rate largely caused by COVID-19 in England and Wales (9) (FIG 1B) .
Across selected European nations, the excess death rate was estimated at 149,447 from week 10, and as of week 18, by the EUROMOMO statistical collaboration (10) . Therefore Pre-emptive triage has been discussed at length during times of war, as an effort to free up beds well ahead of time before large battles are expected to produce scores of wounded soldiers. The danger of applying this concept in healthcare and to clinical trials is not only the potential harm to the individual seeking care under such circumstances, but also that such triage may negatively influence our daily standards of medicine. The shift from patient-centered practice to patient care guided by public health considerations creates great tension (11) . Such prioritization in anticipation of urgency but without the actual firm knowledge of an inevitable and inescapable situation is While we share the notion of desperation and organizational turmoil, we have great concern about the decision of members of the pharmaceutical community to walk away from active clinical trials unless there is a defined scientific reason (e.g. an interaction term between SARS-CoV-2 infection and a certain mode of action of an IMP). In the ethical assessments of trial protocols, risks, benefits and unmet needs are carefully weighed before a clinical trial is approved. While individual benefit cannot be promised to the participants of clinical studies, clinical equipoise demands that any arm of a late stage IMP trial must be sufficiently likely to provide benefit. It therefore follows that withdrawal of such trials and extension arms without direct and clear reason to do so is exposing patients to avoidable harm.
The regulatory bodies in both Europe and the U.S. have addressed the challenges to clinical trials during the COVID-19 pandemic, and offer a variety of solutions for investigators. The EMA has acknowledged that "Extraordinary measures may need to be implemented and trials adjusted due to e.g. trial participants being in self-isolation/quarantine, limited access to public places (including hospitals) due to the risk of spreading infections, and health care professionals being The reduced or limited availability of trial specific healthcare resources also prompts an important discussion about feasibility of endpoint assessments. This discussion has to be led on both the level of the trial conduct (where endoscopy may be difficult to schedule during the pandemic) and the level of practical interventions and testing (where the translation of trial procedures to healthcare may be difficult due to long-term restrictions for access to certain procedures). We need to discuss whether treatment endpoints like mucosal healing which require endoscopy and biopsies can still be used to examine patients in an environment stressed by chronic COVID-19. Therefore, the experiences during the present COVID-19 pandemic should result in accelerated development of validated biomarkers to replace some or all of the morphologic assessments used for treatment guidance by investigators and regulatory bodies.
We work with the patients suffering from IBD and will continue to work with them -neither their disease can walk away nor shall we. Patients depend on new and unlicensed substances as an important resource for their therapy and we consider it unethical to discontinue their clinical trial treatments at this difficult time as a first option. We can and should factor the uncertainty of an interaction between a new therapy and SARS-CoV-2, but to avoid the issue entirely by withdrawing the patient from trials or discontinuing the trials is premature.
Without a doubt, it is time to develop a responsible and unified position to the continuation of clinical trials in chronic IBD during the COVID-19 pandemic. We urge pharmaceutical companies, health care providers, and regulators not to abandon our chronically ill patients or clinical investigators during these challenging times. Instead, we believe that during these current and unprecedented challenges, appropriate resources should be focused on the development of novel and ethical solutions to clinical trial monitoring and endpoints.
A c c e p t e d M a n u s c r i p t