The Beginning - Scurvy
A few words about the history of clinical trials and it’s beginning: aboard the Salisbury ship during a ten-week absence from shore, 80 out of 350 sailors were struck down by scurvy, and Lind’s controlled experiment comparing the relative merits of six treatments in 12 patients began on 20 May 1747.1 Unfortunately, Lind’s therapeutic findings were not immediately accepted into the medical opinion. While his work clearly described experimentally effective treatments, it was only after continuous study and diligent record keeping by Lind and others that a change in political and professional opinion among the authorities directing the naval service adopted the widespread use of lemon juice as an effective treatment for scurvy. This process from proof of concept to mainstream use took forty-two years.1
Next - Smallpox
Less than a decade after the treatment protocol for scurvy was accepted, on May 14, 1796, Edward Jenner inoculated an 8-year old boy with matter from fresh cowpox lesions and two months later, injected the same boy with smallpox to discover that no disease developed. Jenner’s work represented the first scientific attempt to control an infectious disease by vaccination.2 Thanks to the work of Lind and Jenner, and later developments of their endeavors, we do not have to worry about these diseases today.
Fast forward nearly three centuries and clinical researchers, both workers and trial participants, remain steadfast to improve public health and their heroic efforts are just cause for celebration. In this post, we highlight the advancement of medicine made possible through clinical trials and discuss the status of the ongoing COVID-19 clinical trials, bringing recognition to pioneers who stepped up to participate in these studies.
Clinical Trial Accessibility
The ClinicalTrials.gov database contains details of privately and publicly funded clinical studies conducted around the world. This is a useful tool for both patients and researchers to stay informed of current trials. As of 13May2020, the database contained 339,158 research studies across 210 countries. Figure 1 illustrates the percentage of research studies by geographic region, and Figure 2 illustrates the current status of the registered studies. It is nearly impossible to quickly estimate the number of people that the active, interventional clinical trials intend to enroll, but downloading the data from the top 10,000 trials in the database suggest an enrollment number in excess of 14 million subjects. Setting aside one day per year to say “THANK YOU” to the past and current clinical trial volunteers as well as encourage others to follow in their courageous footsteps seems like such a small token in exchange for their service to the advancement of medicine.
Burden of Disease
Despite significant progression in treatment options made possible only through data collected in clinical trials, ischemic heart disease and stroke remain the leading cause of death in the United States and worldwide.3,4 Cancer, diabetes, Alzheimer disease and other dementia; and chronic obstructive pulmonary disease (COPD) are among the top chronic diseases resulting in death annually. In the United States alone, these chronic health conditions cost in excess of $900 billion in medical costs and lost productivity.5 It is impossible to imagine what the death toll would be without the significant advancement in treatment options for chronic diseases made possible through clinical trials. It is equally impractical to list succinctly all contributors to the field. Figure 3 is an abbreviated summary of significant milestones in the available therapies for these chronic diseases.6-12
Estimating the burden of disease imposed by infectious disease is an equally daunting task. Until the discovery and widespread use of vaccines for contagious, infectious diseases, mortality rates were staggeringly high. For instance, the bubonic plague is reported to have killed 20% of London’s population in 1655.13 In 1918, an avian-borne flu, termed the Spanish flu, resulted in 50 million deaths worldwide.13 As of 12May2020, COVID-19 has claimed 285,760 lives worldwide since 31Dec2019.14 In the ClinicalTrials.gov database, there are currently 1409 studies associated with evaluating COVID-19. Of those, 797 are active, interventional studies evaluating a treatment regimen and 60 of those trials are associated with a vaccine with plans to enroll over 40,000 subjects combined. Figure 4 presents a timeline of vaccine development by disease and lists the current vaccine candidates under investigation for COVID-19.15-16
Moving Forward During Pandemic
This year, May 20th serves as a reminder that effective treatments and cures for disease are within our reach. Both the U.S. FDA and EMA have released guidelines to assist researchers in maintaining continuity of their studies while implementing proper safeguards for the clinical trial participants.17-18 Unconventional approaches to evaluating vaccine candidates, such as human challenge studies, are being discussed and debated among the scientific community.19 Unlike traditional vaccine trials, which test vaccine effectiveness in a large group of people who may be naturally exposed to the target virus, human challenge studies for COVID-19 would involve vaccinating subjects with the vaccine candidate and then in controlled fashion, exposing the subject to the live SARS-COV-1 (COVID-19) virus and then monitoring the subject for a defined period of time afterward. This approach risks development of severe disease and possibly death as currently a cure or a proven effective treatment remains unknown, and yet, more than 14,000 people have put their name forward to be considered for this type of trial should an acceptable study design be agreed upon and approved.20 Such altruistic acts of kindness for humanity have not been publicized in the media and clinical trials have not been promoted any more than they are now. More than ever, the spotlight has turned to the clinical research industry for answers as the world anxiously waits for solutions to be discovered to effectively treat or prevent COVID-19 illness. This is indeed an exciting time to be a clinical researcher.
NOTE: Figures 1-4 appear in the image slider at the top of the page.
1. Tröhler, U. (2003). James Lind and scurvy: 1747 to 1795. JLL Bulletin: Commentaries on the history of treatment evaluation, pp. https://www.jameslindlibrary.org/articles/james-lind-and-scurvy-1747-to-1795/
2. Riedel, S. (2005, Jan). Edward Jenner and the history of smallpox and vaccination. Proc (Bayl Univ Med Cent), 18(1), 21-25. doi:10.1080/08998280.2005.1192802
3. The Top 10 Causes of Death. (2018, May 24). Retrieved from World Health Organization: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death
4. Heron, M. (2019). Deaths: Leading Causes for 2017. Centers for Disease Control and Prevention, U.S. Department of Health and Human Services. Hyattsville, MD: National Center for Health Statistics. Retrieved from Leasing Causes of Death: https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm
5. Health and Economic Costs of Chronic Diseases. (n.d.). Retrieved from National Center for Chronic Disease Prevention and Health Promotion (NCCDPHP): https://www.cdc.gov/chronicdisease/about/costs/index.htm#ref1
6. Hajar, R. (2017, Apr-Jun). Coronary Heart Disease: From Mummies to 21st Century. Heart Views, 18(2), 68-74. doi:10.4103/HEARTVIEWS.HEARTVIEWS_57_17
7. Kandaswamy E and Zuo L (2018). Recent Advances in Treatment of Coronary Artery Disease: Role of Science and Technology. Int J. Mol Sci, 19(424), doi:10.3390/ijms19020424.
8. History of Dementia Research. Retrieved from The University of Queensland, Queensland Brain Institute. https://qbi.uq.edu.au/brain/dementia/history-dementia-research
9. Ali R. Rezai, et al., Noninvasive hippocampal blood−brain barrier opening in Alzheimer’s disease with focused ultrasound. Proceedings of the National Academy of Sciences Apr 2020, 117 (17) 9180-9182; DOI: 10.1073/pnas.2002571117
10. Evolution of Cancer Treatments: Surgery. Retrieved from American Cancer Society. https://www.cancer.org/cancer/cancer-basics/history-of-cancer/cancer-treatment-surgery.html
11. Milestones in Cancer Research and Discovery. Retrieved from National Institute of Health/National Cancer Institute. https://www.cancer.gov/research/progress/250-years-milestones
12. Science. Progress. Hope. Retrieved from the American Diabetes Association. https://www.diabetes.org/resources/timeline
13. Pandemics That Changed History. (2020, April 30). Retrieved from HISTORY: https://www.history.com/topics/middle-ages/pandemics-timeline
14. COVID-19 situation update worldwide, as of 12 May 2020. Retrieved from European Centre for Disease Prevention and Control: https://www.ecdc.europa.eu/en/geographical-distribution-2019-ncov-cases
15. Plotkin S. History of vaccination. Proc Natl Acad Sci U S A. 2014;111(34):12283‐12287. doi:10.1073/pnas.1400472111
16. Vaccine Timeline. Retrieved from Immunization Action Coalition. https://www.immunize.org/timeline/.
17. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency. Guidance for Industry. Retrieved from https://www.fda.gov/media/136238/download
18. GUIDANCE ON THE MANAGEMENT OF CLINICAL TRIALS DURING THE COVID-19 PANDEMIC. Version 3. Retrieved from https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf
19. Eyal, N., Lipstich, M., & Smith, P. G. (2020). Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure. J Infect Dis., 1752-1756. doi: 10.1093/infdis/jiaa152
20. Ramgopal, K. (2020, May 10). Why have 14,000 people volunteered to be infected with coronavirus? Retrieved from https://www.nbcnews.com/health/health-news/why-have-14-000-people-volunteered-be-infected-coronavirus-n1203931