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- Page navigation anchor for RE: Generating randomized trial evidence to optimize treatment in the COVID-19 pandemicRE: Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic
We agree with Cheng et al. regarding the need to generate robust evidence through randomized trials.(1) However, we note that inclusion of pregnant individuals is conspicuously absent from this call to action. Of COVID-19-related investigations registered on clinicaltrials.gov, 28/1486 (1.9%) include pregnancy and 4/28 involve pharmacologic interventions; granting pregnant individuals access to a mere 0.3% of all COVID-19-related intervention trials!(2)
Exclusion of pregnant individuals from trials originated from the perspective of beneficence and protection of the vulnerable,(3) a safeguard predicated on the obsolete assumption of incapacity to provide informed consent. This practice now directly contravenes the right to autonomy and self-determination.(3)
The Global Forum on Bioethics in Research (GFBR) denounced the classification of pregnant individuals as vulnerable, given absence of evidence that the pregnant state confers cognitive impairment or invokes undue susceptibility to harm.(4) Omitting pregnant individuals from the controlled research environment magnifies vulnerability by shifting experimentation onto the clinical stage,(4) where interventions necessary for preservation of maternal and fetal health are instituted in absence of trial data; robbing this population of access to a platform accepted as the gold-standard of evidence-based medicine.
The Government of Canada called for consideration of inclusion of pregnant individuals in t...
Show MoreCompeting Interests: None declared.References
- Matthew P. Cheng, Todd C. Lee, Darrell H.S. Tan, et al. Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic. CMAJ 2020;192:E405-E407.
- U. S. National Library of Medicine. ClinicalTrials.gov Available: https://clinicaltrials.gov/ct2/results?cond=COVID&term=pregnancy&cntry=&state=&city=&dist=&Search=Search Accessed: 14 May 2020.
- Park SS, Grayson MH. Clinical research: protection of the "vulnerable"? J Allergy Clin Immunol. 2008;121(5):1103-7.
- Global Forum on Bioethics Research. Ethics of research in pregnancy: Meeting report. Buenos Aires, Argentina. Available: http://www.gfbr.global/wp-content/uploads/2017/04/GFBR-2016-report-ethics-of-research-in-pregnancy-FINAL.pdf. Accessed: 25 April 2020.
- Government of Canada. Guidance Document: Considerations for Inclusion of Women in Clinical Trials and Analysis of Sex Differences. Available: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guid
- Page navigation anchor for RE: Generating randomized trial evidence to optimize treatment in the COVID-19 pandemicRE: Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic
Cheng and colleagues highlight the importance of evaluating potential therapies for COVID-19 within randomized controlled trials (RCTs).(https://www.cmaj.ca/content/192/15/E405) One major untapped resource for research is our community hospitals, which provide care to the majority of Canadians1. The ability to recruit patients from community hospitals would accelerate scientific progress by expanding the pool of patients enrolled in RCTs. Moreover, enrolling a broader cross-section of patients would lead to more generalizable results. Finally, during a pandemic, it is impossible to predict which hospitals will see a surge of cases. By expanding the network of hospitals that are capable of participating in clinical trials, the likelihood of appropriate patients being enrolled is greatly increased.
There are tremendous barriers to research implementation during a pandemic2,3, and this is especially true in community hospitals. These include lack of pre-existing research infrastructure and research staff, the need to redirect resources and redeploy staff to frontline clinical work, and the desire to protect research staff from contact with infected patients as well as to conserve personal protective equipment4.
An important facilitator of community hospital-based pandemic research is previous research experience. Academic-community partnerships can help with this, as can networks that link community hospita...
Show MoreCompeting Interests: None declared.References
- Matthew P. Cheng, Todd C. Lee, Darrell H.S. Tan, et al. Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic. CMAJ 2020;192:E405-E407.
- Gehrke, P. et al. Fostering community hospital research. Cmaj 191, E962–E966 (2019)
- Angus DC. Optimizing the trade-off between learning and doing in a pandemic. JAMA Netw Open [Internet]. 2020 March
- Cook, DJ, Marshall JC, Fowler RA. Critical illness in patients with COVID-19. JAMA Netw Open
- Ranney ML, Griffeth V, Jha AK. Critical supply shortages — the need for ventilators and personal protective equipment during the Covid-19 pandemic. N Engl J Med [Internet]. 2020 March
- Page navigation anchor for RE: Ethics review in the pandemic setting: the role of a centralized system in the emergency response to emerging infectionRE: Ethics review in the pandemic setting: the role of a centralized system in the emergency response to emerging infection
Cheng et al address the necessity of research to address the challenge of SARS-CoV (1). Research about a novel large-scale outbreak of disease constitutes an integral part of the emergency response to the outbreak. Studies are often conducted across multiple locations and must be initiated quickly. High-quality and expedient research ethics review is required before such research can commence .The preparedness of systems to support efficiency and quality is challenged by the outbreak and the importance heightened. Clinical Trials Ontario (CTO) is an example of a prepared system.
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CTO is a not-for-profit corporation funded primarily by the Government of Ontario. It began in response to the demands of sponsors and investigators for timely and efficient ethics review of clinical trials. It supports a single ethics review conducted by one of 19 pre-qualified boards and applicable to any of 106 hospitals or universities across the province. The 11 COVID-19 multi-centre studies submitted to the CTO web-based digital platform (2) prior to the Easter holiday weekend (8 more arrived over the weekend) have required a median 6 days for provincial approval; each centre application (they may be reviewed and approved in parallel), a further 2 days. Common review issues related to COVID-19 surround testing (resource limitations and reporting to public health authorities), in-person contact and protections, and ensuring participants are not approached for multiple competing...Competing Interests: Saginur is a past member of the Board of Directors of Clinical Trials Ontario; Marlin is Chief Executive Officer of Clinical Trials OntarioReferences
- Matthew P. Cheng, Todd C. Lee, Darrell H.S. Tan, et al. Generating randomized trial evidence to optimize treatment in the COVID-19 pandemic. CMAJ 2020;192:E405-E407.
- 2. Accessible at ctontario.ca
- Page navigation anchor for Impact of COVID-19 on pediatric clinical research in FranceImpact of COVID-19 on pediatric clinical research in France
As stated by Cheng and colleagues, temptations to use unproven medications/strategies and to get away from scientific evidence are high when facing the frightening COVID-19 pandemic. Most medical and scientific communities reacted promptly to better fight against the disease therefore challenging standards especially in Pediatric Clinical Research (PCR).
PEDSTART (https://www.pedstart.org/en) is the national network of French PCR. A task force has been created to gather all national research initiatives and anticipate the consequences of COVID-19 on PCR. At present, we identify no less than15 projects at different stages of maturity involving pediatric patients. Overlap between studies is frequent and multiplicity of trials may jeopardize relevant approach. On a practical standpoint each pediatric clinical investigation center had to reorganize itself rapidly, while meeting a triple requirement of: (i) limiting travel and contact with patients, (ii) protecting hospital staff from infection, and (iii) reducing the activity of the hospital to ensure there are enough staff and beds for COVID-19 infected patients. Negative and positive effects are observed. While COVID-19 strengthens team cohesion and involvement, we have to face decrease in PCR activity. Investigational medicinal product’s supply management and good clinical practices will be challenged by unprecedented adaptations of research infrastructure.
This period...
Show MoreCompeting Interests: None declared.References
- , , , et al. Impact of COVID-19 on pediatric clinical research in France. 2020;:-.
- Page navigation anchor for RE: COVID sample sizeRE: COVID sample size
Cheung et al. (2020) warned that under-powered studies that committed a type II error will discourage clinicians to use an effective treatment.1 I agreed with this argument. Since the number of published clinical trials on COVID-19 patients was increasing rapidly, I have reviewed all these trials published from 1st January 2020 to 25th March 2020 indexed in PubMed and assessed their quality of sample size calculation.
A total of 374 papers were identified by the search and 4 papers were trials. In general, the quality of sample size calculation was not acceptable. One did not justify the sample size.2 One stated that the estimated effect size as “detecting a reduction of 40% between the treatment and nontreatment groups” but the Cohen’s d effect size should be provided instead.3 One did not explicitly state the non-zero assumption of the control group effect 4 (that they assumed the effect of the control group would be around 5% according to the Fliess formula with continuity correction used by the authors 5). The remaining study did provide the effect size estimation, but the sample size calculated in the paper deviated from that calculated using the standard formula by 6% (the percentage of patients reaching the outcome within the study period should be 71.1% as calculated according to the assumptions given by the authors, but they overestimated that to be 75% in the paper)...
Show MoreCompeting Interests: None declared.References
- Wu CN, Xia LZ, Li KH, et al. High-flow nasal-oxygenation-assisted fibreoptic tracheal intubation in critically ill patients with COVID-19 pneumonia: a prospective randomised controlled trial. Br J Anaesth 2020:article in press.
- Zhou YH, Qin YY, Lu YQ, et al. Effectiveness of glucocorticoid therapy in patients with severe novel coronavirus pneumonia: protocol of a randomized controlled trial. Chin Med J 2020:article in press.
- Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020:article in press.
- Fleiss JL, Tytun A, Ury HK. A Simple Approximation for Calculating Sample Sizes for Comparing Independent Proportions. Biometrics 1980;36:343-46.
- Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. New Engl J Med 2020:article in press.