Clinical Researcher—December 2021 (Volume 35, Issue 9)

PEER REVIEWED

Mostafa Salah, MSc, CCRP, ACRP-CP; Ola Elrouby, MSc; Mohamed Ayman, BPharm; Rehab Ahmed, BPharm

 

The urgent need for safe and effective treatment for COVID-19 infection and its related complications has driven the design of clinical trials aimed at finding a solution for this critical pandemic through screenings of already approved drugs and investigations of new candidates. The proper study protocol design could affect the validity of the results and the conclusions extracted from the study.

Background

According to the International Council for Harmonization’s guidelines for Good Clinical Practice, any clinical trial should be conducted by following a previously approved protocol. This protocol demonstrates the detailed procedures for conducting the trial to achieve overall quality and ensuring validity of the study’s conclusions.{1}

As the COVID-19 crisis lingers into yet another year, there is an urgent need for conducting well-designed and well-powered clinical trials for scientific evaluation of potential COVID-19 therapies.{2} In addition to the authors’ own experiences in managing and conducting many COVID-19 trials, we have revised many published COVID-19 studies and regulatory authorities’ guidelines regarding the development of products for treatment of the disease. What follows are several lessons learned from these experiences which we hope will help other researchers in designing their own proper clinical trial protocols for COVID-19 treatments.

Critical Points to be Considered Before and During Clinical Trial Protocol Development

Scientific rationale: The emerging pandemic allowed some sponsors and regulatory authorities to waive some applications for treatments from the normal development and approval pathway. Although this may shorten the pathway required for approval, some steps should not be waived. As an example, many pandemic-related clinical trials were initiated before conduction of proper preclinical studies to determine the most appropriate dose required in human subjects.

Further, many clinical trials were initiated based on docking or in-vitro studies or observations from some practitioners. This shortened pathway resulted in the investigation of many drugs without proper previously accepted pharmacokinetic/pharmacodynamic (PKPD) profiles. In one case, it was found that the required plasma concentration to achieve therapeutic effects could not be reached with a safe human dose.{3} This goes to show that clinical studies should be preceded by dose-response studies in animal or human models.

Endpoints: COVID-19 clinical trial protocols should feature endpoints which target the overall clinical status of patients, mortality rates, or need for intensive care unit admissions rather than targeting polymerase chain reaction (PCR) quantitative changes.{4}

PCR negativity is not a proper endpoint, especially in Phase III trials, as there is poor relation between the clinical outcome and the results of patients’ PCR results. It was reported that many patients might still display SARS-CoV-2-positive PCR results up to weeks or months after clearance of the disease.{5} However, a quantitative PCR endpoint which depends on viral RNA level assessment might be useful in a Phase II clinical trial as a proof of concept for the efficacy of the investigational drugs. Another possible way is to perform viral conductivity assays to characterize the impact of treatment on shedding of cell culture infectious virus.

The most suitable way to detect the clinical effect of the investigational products, as we mentioned previously, should depend on the clinical picture of the patients and the disease progression status. The ideal endpoint to capture disease progression or improvement is the ordinal scale developed by the World Health Organization (WHO), which has already been used in many clinical studies, such as the SOLIDARITY trial.{6}

Monitoring of symptoms is important in COVID-19 trials but is better considered as part of secondary endpoints (especially in non-mild patients), as the administered COVID-19 treatment standard of care, which already contains several agents, may mask such symptoms of the disease as fever, cough, and arthralgia and bias the results of the study.

In mild out-patients, it may be acceptable to rely only on symptoms as an endpoint with the application of scoring for symptom severity at baseline and through the study process, as long as one considers how clinical findings show that certain symptoms (e.g., cough, fatigue, decreased sense of taste and sense of smell) may take longer to resolve in comparison to other symptoms.{7}

Further, change in lung lesions cannot be considered a suitable endpoint, as the published literature reveals that change may persist for a long time after the absence of all clinical symptoms and improvement in the patient’s overall status has been achieved. In addition, lungs may take longer time for complete healing,{8} and it may be unethical to examine the patient several times by CT, as this may impact participant safety.

Meanwhile, when targeting detection of changes in oxygen saturation, the study design should take into consideration measurements of the saturation after removal of the patient’s mask (room air recording). Recording oxygen saturation values when patients are masked may give higher values without the availability of a predictive tool to identify or estimate the true oxygen saturation percentage of the patient.

Finally, lab biomarkers such as IL-6, D-dimer, lymphocytes, or ferritin could be considered a sensitive endpoint to detect the severity of the disease in critical and severe infections, but these biomarkers may be of no value in studies for mild to moderate cases, as many reports stated that those patients might lack biomarker abnormalities through the disease course.{9}

Monitoring: The protocol and/or monitoring plan should consider the difficulty of performing onsite monitoring during the conduction of the study. A risk-based monitoring approach should be implemented to ensure verification of data and proper monitoring of the study conduction. The protocol should also specify the key critical data being sought in order to facilitate the monitoring process and achieve balance between accuracy and validity. This approach depends on the availability of certain electronic resources to enable centralized or remote monitoring.{10}

Population: The protocol should clearly detail the eligibility criteria with consideration of the following points:

• Application of proper classification rules for disease severity, which can be extracted from either U.S. Food and Drug Administration guidelines{4} or WHO guidelines.{11} The inadequate categorization of patients may affect the validity of results or prevent the proper detection of the treatment effects due to the variability in subgroups’ baseline difference, disease progression, or co-morbidities.
• The inclusion criteria should be extended to include patients with co-morbidities and advanced age, as these patients are more susceptible to disease progression with higher mortality rates.
• Studies of false-negative PCR results from respiratory samples for SARS-CoV-2 demonstrated that false-negative rates up to 30% may occur, which could be due to reasons including suboptimal specimen collection, testing too early in the disease process, low analytic sensitivity, inappropriate specimen type, low viral load, or variability in viral shedding. To overcome the impact of these false-negative results on the rate of enrollment, regulatory authorities in cooperation with researchers should apply other eligibility parameters to confirm COVID-19 infection, such as clinical symptoms or radiological chest scans. A useful criteria for clinical diagnosis of COVID-19 was recently published with suitable specificity and sensitivity in comparison to the PCR technique.{12}
• In general, the allowed time limit for onset of symptoms in enrolled patients should be prespecified in the protocol. Depending on the type of investigational products and their mechanisms of action, the allowed time limit for eligibility could be defined. Example: for antiviral drugs, it is better to enroll patients early, with up to 10 days from symptoms onset to capture the effect of the drug during the viremia phase.{13}

Concomitant medication: The protocol should closely address the PK/PD interactions between any of the investigational products and any agent from the standard of care protocol, as many drugs have been found to affect the efficacy of investigational products after further study.{14}

Conclusion

Proper protocol development is critical to ensure the validity and reproducibility of clinical trial results, especially in pandemic emergencies such as we’ve seen from COVID-19 infection. Large and accurate literature reviews should be performed to collect all available data to strengthen the design of protocols. Sponsors and researchers should consider the points raised above during the protocol development phase.

References

1. ICH GCP E6(R2) guidelines: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
2. Rai SN, Qian C, Pan J, Seth A, Srivastava DK, Bhatnagar A. 2020. Statistical design of Phase II/III clinical trials for testing therapeutic interventions in COVID-19 patients. BMC Medical Research Methodology 20:Article 220.
3. Bray M, Rayner C, Noël F, Jans D, Wagstaff K. 2020. Ivermectin and COVID-19: A report in Antiviral Research, widespread interest, an FDA warning, two letters to the editor and the authors’ responses. Antiviral Res 178:104805. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172803/
4. FDA guidelines: COVID-19: Developing Drugs and Biological Products for Treatment or Prevention Guidance for Industry. 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/covid-19-developing-drugs-and-biological-products-treatment-or-prevention
5. Public Health Agency of Canada guidance for repeated PCR testing in individuals previously positive for COVID-19. 2020. https://www.canada.ca/en/public-health/services/diseases/2019-novel-coronavirus-infection/guidance-documents/repeated-pcr-testing-individuals-previously-positive-covid-19.html
6. WHO interim analysis results. 2021. Repurposed Antiviral Drugs for Covid-19 — Interim WHO Solidarity Trial Results. N Engl J Med 384:497–511. https://www.nejm.org/doi/full/10.1056/NEJMoa2023184
7. FDA guidance: Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment Guidance for Industry. 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/assessing-covid-19-related-symptoms-outpatient-adult-and-adolescent-subjects-clinical-trials-drugs
8. Hefeda 2020. CT chest findings in patients infected with COVID-19: review of literature. Egyptian Journal of Radiology and Nuclear Medicine 51:Article 239.
9. Malik P, Patel U, Mehta D, Patel N, Kelkar R, Akrmah M, Gabrilove JL, Sacks H. 2021. Biomarkers and outcomes of COVID-19 hospitalizations: systematic review and metanalysis. BMJ Evidence-Based Medicine 26(3). https://ebm.bmj.com/content/26/3/107
10. FDA guidance: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers Guidance for Industry. 2019. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/risk-based-approach-monitoring-clinical-investigations-questions-and-answers
11. WHO guidance: COVID-19 clinical management. 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-1
12. Cadegiani FA, Zimerman RA, de Souza BC, McCoy J, E Costa RAP, Wambier CG, Goren A. 2021. The AndroCoV Clinical Scoring for COVID-19 Diagnosis: A Prompt, Feasible, Costless, and Highly Sensitive Diagnostic Tool for COVID-19 Based on a 1757-Patient Cohort. Cureus 13(1):e12565.
13. Tana C, Biao S, Jian LY, Meizhu L, Liu CJ. 2020. SARS-CoV-2 viremia may predict rapid deterioration of COVID-19 patients. The Brazilian Journal of Infectious Diseases 24(6):565–9.
14. New potential interaction with emergency COVID-19 medicine remdesivir. 2020. Nature public health emergency collection. Reactions Weekly 1810(1):3. doi:10.1007/s40278-020-80023-6

Mostafa Salah, MSc, CCRP, ACRP-CP, (mostafa.salah@tcdmena.com) is Clinical Project Manager and Scientific Affairs Manager with TCD MENA in Cairo, Egypt.

Ola Elrouby, MSc, is Managing Director with TCD MENA.

Mohamed Ayman, BPharm, is a Clinical Monitor with TCD MENA.

Rehab Ahmed, BPharm, is a Clinical Monitor with TCD MENA.