Scientificity is essential to the effectiveness of clinical research results. To research the off-label use of CQ and HCQ, it is necessary to carefully study the instructions for these drugs, obtain and consider the latest supplementary instructions for their use, and design the research plan accordingly.

When considering using CQ and HCQ to treat COVID-19, it is necessary to fully consider the indications, usages, dosages, precautions, adverse reactions, contraindications, drug interactions and possible risks. In view of the above considerations, researchers should refine their plans and measurements, clarify the specific indicators, and, for the long-term follow-up of the clinical responses, develop medical countermeasures. At the same time, in accordance with the scientific requirements, a gold standard for evaluating interventions involving CQ and HCQ needs to be established, and alternative research designs, such as adaptive designs and stepwise designs, should be explored. Before using alternative research designs, the advantages and disadvantages must be carefully evaluated to minimize the risk to the subjects.

The sample sizes needed in studies of CQ and HCQ are uncertain. According to the developing trends of the pandemic, it is necessary to recruit a large numbers of clinical research subjects; research should not be wasted due to an insufficient sample size. At present, countries are gradually gaining control over the pandemic, and it is also important to ensure that there are enough subjects in CQ and HCQ trials to prevent the unnecessary exposure of subjects to risk.

When determining patients for inclusion, it is important to consider that CQ should be used with caution in patients with the following conditions: Liver and kidney insufficiency, heart disease, severe multitype erythema, hematoporphyria, psoriasis, and psychosis. Other considerations include the following: (1) “Providers should be careful when applying it for patients with liver disease”; (2) “It is particularly dangerous for patients with porphyria”; (3) “Patients lacking glucose 6-phosphate dehydrogenase are at great risk of hemolysis”; (4) “Children are particularly sensitive to the toxicity of this drug”; and (5) “It can aggravate the onset of psoriasis or promote the recurrence of psoriasis”. The clinical precautions needed when using HCQ are clear: “All patients should undergo ophthalmological and ECG examinations” and “Patients with the following conditions should increase their frequency of eye examinations”: (1) Patients with a daily dose exceeding the ideal body weight of 6.5 mg/kg (using the absolute body weight as a dosing guide can cause overdosing in obese patients); (2) Patients with renal insufficiency; (3) Patients with a cumulative dose exceeding 200 g; and (4) Patients with adverse reactions”. In addition, precautions in the “elderly” population should be fully considered with regard to patient exclusion or as early withdrawal criteria to prevent their incorrect inclusion. At the same time, there must be a withdrawal standard that takes into account the rapid progression of the disease and sudden changes in each stage to protect the safety and rights of the subjects to the greatest extent. All patients who meet the criteria should enter the selection process for screening. Selected patients must strictly abide by a program’s selection and exclusion criteria. Criteria that are too loose will lead to the inclusion of patients who are not suited for the program. Criteria that are too strict actually added new exclusion criteria and eventually led to so-called "super selection". There will be bias in both cases. To ensure the speed and quality of patient selection, although it is possible to mobilize more doctors to recommend patients, it is best to focus on a few doctors who understand the plan and are available at any time. It is important for these doctors to ask for clarification when there is a paradox in the exclusion criteria. When seeking clarification, the PI of a unit should be contacted before the inspector. If there is a period of uncertainty regarding the inclusion of a patient in a trial, the treatment of the patient's condition should be the primary focus, and the diagnosis and treatment should not be delayed due to selection. In the event of serious adverse reactions such as cardiotoxicity, subjects should be considered for early withdrawal. We should also pay attention to people with rare diseases where off-label drugs for COVID-19 might lead to severe complications, such as patients with neuromuscular diseases[10].

It is important to distinguish among mild, severe, slowly developing, and urgent symptoms of COVID-19 to determine the status of the subjects and the specific timing and conditions indicating the use of CQ and HCQ. For example, patients with mild COVID-19 should receive the medication at the beginning of the diagnostic process; when hospitalized, patients with severe COVID-19 should receive it before intubation; and patients experiencing a life-threatening emergency should receive it after intubation. In the above situation, the corresponding evaluation index should be set after the medication is administered. The main evaluation index used for patients with mild COVID-19 is the cure rate or the rate of conversion from severe COVID-19; the main evaluation indicator for critical patients is the case fatality rate. In emergencies, the clinical recovery time can be used as a surrogate endpoint. At the same time, the dosage of a patient's medication at each stage, the rate of ventilator use after drug treatment, and whether drug treatment was combined with other medications should be considered important evaluation indicators. It is necessary to compare the evaluation indicators among patients with various symptoms who have and have not been treated with CQ and HCQ to comprehensively determine the benefits of the medications.

We need to reasonably evaluate and anticipate the risks and benefits of the research. The expected benefits should be greater than the risks, and the subjects should be fully informed of the risks involved in the research. Appropriate strategies should be adopted as much as possible to minimize the risks to patients. It is important to identify the possible risks and symptoms of adverse events in each stage of the process related to treatment with CQ and HCQ to formulate targeted risk mitigation measures to carefully control and reduce the risks.

There are clinical trials reporting that taking high doses of CQ and HCQ carries the risk of clinical arrhythmia. According to the reports, a total of 81 subjects participated in a randomized double-blind HCQ trial for the treatment of COVID-19 in Brazil. Approximately half of the patients took 450 mg twice a day for 5 consecutive days, while the other half took 600 mg a day (high-dose group). On the third day of the trial, some patients in the high-dose group experienced severe arrhythmia, and 11 people died; the investigator had to terminate the trial as soon as possible[11]. In addition, there have been studies showing that the combination of HCQ or CQ with azithromycin can cause cardiac safety issues; one such study was an analysis of HCQ use in more than 950000 patients from 6 countries. The results showed that the current HCQ recommended dose for rheumatoid arthritis is safe; when azithromycin is used at the same time, the QT interval may be prolonged or even torsade de pointes tachycardia, resulting in sudden death. This suggests that caution should be used when combining medications. Current reports show that SARS-CoV-2 may affect the heart muscle and cause myocarditis. Individual autopsy reports suggest that the myocardium is infiltrated by interstitial mononuclear inflammatory cells, indicating that the heart tissue is infected. Severe myocarditis with decreased myocardial contractile function has also been reported in COVID-19 patients. Studies of cardiac biomarkers have also shown that the incidence of cardiac damage in hospitalized patients is high. COVID-19-induced electrolyte disorders (such as hypokalemia and hypomagnesemia) should not be understated, as they can explain why COVID-19 patients are at high risk for ventricular arrhythmias when treated with HCQ. The cytokine storm can also have a prolonging effect on the QT interval[12].

However, there are major uncertainties about the pathogenesis of COVID-19. Despite our efforts to reduce risks, serious harm may still occur. Therefore, subjects should be provided with high-quality supportive care (including necessary intensive care), long-term follow-up (to detect any lasting injury), and adequate compensation for any injury that occurs to fully protect their rights and interests.

Coordinated research is intended to ensure that clinical research-related public health benefits are achieved with the greatest possible safety and efficiency. Therefore, research should be coordinated with public health agencies to prevent unduly compromising the local public health response to COVID-19. Research should also be fully supervised by the relevant authorities (including the World Health Organization when appropriate), and adequate communication and coordination with regulatory agencies should be ensured to maximize safety. During early coordination with regulatory agencies, attention should also be paid to the data and results regarding research on the off-label use of CQ and HCQ.

The research team is the main group involved in conducting drug trials. With regards to drug research conducted during a pandemic, the clinical qualifications, scientific research ability and industry influence of the team members determine the effectiveness of the research.

In terms of personnel qualifications, the main investigator should have clinical experience in the use of CQ, HCQ, etc. The research team members should have the appropriate qualifications and clinical research experience and should have received training on drug clinical trial quality management practices and infectious disease protective measures. In addition, a certain number of clinically experienced pharmacists and nursing staff should participate.

In terms of the division of responsibilities, the main researchers should adequately delegate the responsibilities and coordinate the research team, and reasonably allocate the time and energy needed for the clinical research and clinical treatment, including designing the research plan, obtaining informed consent, screening patients for enrollment, acquiring clinical specimens, collecting data in the field, filling in case report forms, performing the statistical analysis, etc. All processes should be carried out by the specific personnel responsible. The China national medical aid team in Hubei can be considered as an example. The clinical trial is led by the academician, and the vice president is directly responsible for the trial. The chief physician of the Department of Respiratory Medicine and Critical Care implements the specific treatments and monitors changes in the patients’ conditions, and the clinical pharmacology trial institution conducts the trial. With regard to data management and analysis, the entire team has a comprehensive relevant professional background, and there is a clear division of labor and a mechanism to ensure smooth communication and collaboration.

In addition to referring to the criteria for the inclusion, exclusion and withdrawal of subjects specified in the study design, the selection of subjects should also follow the principle of fairness. The principle of fairness is one of the four basic principles of medical ethics. Fairness in research plays an important role in maintaining trust in the relationship between the public and medical researchers. During a pandemic, the principle of fairness is particularly important.

Researchers, sponsors and ethics committees need to ensure that the risks and benefits to subjects are fairly balanced. During a sudden infectious disease pandemic, potentially effective interventional clinical research may be limited. Therefore, researchers should recruit subjects fairly and pay special attention to the inclusion or exclusion of subjects from special groups (such as medical personnel with confirmed infections). There should be sufficient and reasonable rationale behind the selection of subjects. Equity is also reflected in the fact that the subjects should have equal access to the results of the research, and the subjects’ welfare should be ensured after the trial.