With the need for fast treatment options, for COVID-19 and other diseases, is it necessary to re-approve drugs already approved by the FDA?
by Timothy J. Sellati, Ph.D., Chief Scientific Officer, Global Lyme Alliance
There is a rush to find effective treatments for COVID-19, and with good reason. Right now, the virus is moving faster than science, and too many people are suffering and dying. But must we wait for science? The question faced by scientists, physicians, and patients is—is it better to wait and use drugs that have been scientifically vetted for treating COVID-19 or should we immediately use drugs that have been vetted and used in treating other diseases, and show positive, yet anecdotal, results with COVID-19? Both have benefits and both have risks.
While many drugs that were originally created to treat a specific illness have found new roles in successfully treating other diseases, it was not without rigorous, scientifically sound clinical trials. For example, Thalidomide which was originally developed in the 1950s to relieve nausea in pregnant women (unfortunately yielded devasting side effects), was later discovered to aid in the treatment of multiple myeloma. Is the same type of finding possible in treating COVID-19?
What’s behind the Hydroxychloroquine buzz?
A mad rush is on to find ways to treat desperately ill COVID-19 patients. A French study provided tantalizing, though anecdotal, evidence that Hydroxychloroquine (HCQ, commonly known by the brand name Plaquenil), when coupled with the macrolide antibiotic Azithromycin (AZ), might help patients clear the virus SARS-CoV-2 sooner.1 HCQ is approved for treating malaria, rheumatoid arthritis, and lupus.
Unfortunately, this off-label, non-randomized study suffered from both design flaws and decisions regarding inclusion and exclusion of study participants that undermined the strength of the conclusions drawn from the work. For example, the study was hampered by limited patient enrollment, it lacked critical control groups, and the results from three patients, whose symptoms worsened and were sent to intensive care, were not included in the statistical analysis used to evaluate treatment effectiveness.
Based upon the aforementioned study design issues and potentially serious side effects associated with HCQ, the American Medical Association’s president, Dr. Patrice Harris, said she personally would not prescribe the drug for a coronavirus patient, saying the risks of severe side-effects were “great and too significant to downplay” without large studies showing the drug is safe and effective.2 The need for more testing has also been espoused by Dr. Anthony Fauci (Director, National Institute of Allergy and Infectious Diseases). According to Dr. Fauci Americans should not assume HCQ is a “knockout drug”.3 He goes on to say that “We still need to do the definitive studies to determine whether any intervention, not just this one, is truly safe and effective.”.
Despite the aforementioned concerns, doctors are already prescribing the malaria drug to patients with COVID-19, a practice known as off-label prescribing, and severe shortages of the drug have limited its availability to patients suffering from autoimmune disorders such as rheumatoid arthritis and lupus.
What we can agree on, is if a new drug, like HCQ, is being prescribed to COVID-19 patients, it’s imperative they be closely monitored both for potential side effects and treatment effectiveness.
Why conduct a new clinical trial if a drug is already working?
Clinical trials are an important step in discovering new treatments as well as new ways to detect, diagnose, and reduce the risk of disease. Trials can determine whether a particular drug, both new and existing, is safe and at what dosages, and for which patients the treatment may or may not be effective and why. Perhaps most importantly, clinical trials also help doctors and patients decide if the side effects of a new treatment are acceptable when weighed against the benefits offered by the new treatment.
In an ideal clinical trial, the control or placebo group (which does not receive drug) and treatment group (which does receive the drug under investigation) should be as similar as possible. Patients should be of similar age and gender ratio, be equally sick at the start of treatment and analyzed in the same way. The only difference between the two groups should be whether the patients received treatment or not. However, in the French study, the control and treatment groups differed in various ways from each other. Scientists call those confounding factors, factors other than the treatment that are different between the controls and treated patients, and that might explain the different outcomes.
Several additional clinical trials have been initiated to overcome these shortcomings and test if HCQ as well as other traditional antiviral drugs truly help COVID-19 patients. Many of these studies are ongoing and in the absence of reported randomized trials, there is an urgent need to evaluate real-world evidence related to outcomes with the use of HCQ with or without AZ or other macrolides. Using an international, observational registry across six continents a group of researchers assessed 96,032 patients with COVID-19, of whom 14,888 were treated with HCQ with or without a macrolide.4 After controlling for age, sex, race or ethnicity, underlying comorbidities, and disease severity at baseline, no evidence of benefit of HCQ was found when used either alone or with a macrolide. In fact, researchers estimated that the death rate attributable to use of HCQ with or without AZ is roughly 13% versus 9% for patients not taking them. Thus, while other studies remain to be completed the safety and efficacy of HCQ is more in doubt than not. In fact, FDA recently revoked emergency use authorization for Hydroxychloroquine.
Are there parallels between off-label treatment for COVID-19 and Lyme disease, specifically post-treatment and chronic Lyme?
Absolutely. It is not uncommon to find Lyme-treating physicians prescribing HCQ to their patients. However, with the exception of a case report from 1981 and a study in 2003, there is limited evidence in the peer-reviewed clinical literature speaking to the efficacy of HCQ in treating chronic Lyme disease. In fact, in the 2003 study conducted by Sam T. Donta, M.D., chronic Lyme patients who had been on HCQ or macrolide antibiotic alone had experienced little or no improvement.5
More recently, several researchers have conducted screens of chemical libraries to identify novel drugs to treat Lyme disease.6,7,8 One compound in particular, the FDA-approved drug Disulfiram, which has been used for 40 years to treat alcoholism, was shown in in vitro (test tube-based) experiments to kill Borrelia burgdorferi, the causative bacterial agent of Lyme disease.7 A subsequent limited case study suggested Disulfiram could potentially treat Lyme disease in humans.9 Unfortunately, like HCQ, Disulfiram can have serious side effects, and clinical trials to evaluate its safety and efficacy specifically in Lyme patients have yet to be completed. Nevertheless, there has been a ‘run’ on Disulfiram, thus limiting supplies, because Lyme-treating physicians are forging ahead with its use, some Lyme patients are even self-medicating without the benefit of medical oversight, and the potential risks are yet to be fully appreciated. But given that is providing relief for many patients, it’s a difficult balancing act between patient needs and scientific rigor.
Where does this leave us?
One might persuasively argue for the compassionate use of novel drug therapies for the treatment of seriously ill COVID-19 patients on respirators. This is especially true with mortality rates in the range of 1% (overall) to 2.3% in China and 7.2% in Italy.10 Conversely, one could argue that the risks of using treatment options not subjected to clinical validation in Lyme disease patients, where mortality rates are much lower, outweigh the potential benefits.11But to the patient who is suffering, they may disagree.
The road to find effective treatments for Lyme disease has been long. It’s promising, however, that there are multiple clinical trials and observational studies in progress specific to Lyme treatment, including a clinical trial for Disulfiram as well as other novel treatment regimens.
As a scientist, I have always leaned toward evidence-based results. As a person who works with Lyme patients every day and is witnessing the impact of COVID-19, I know we must find a happy medium, that offers safe and effective treatment to patients in a timely manner.
Related GLA Science Blogs
Is the Clinical Trials Process Working?
COVID-19: Is a Vaccine the Answer?
Research Sharing: What Can Lyme Disease Can Learn from Skin Cancer?
Pandemics, Ecology, and Food Production: Is There a Connection?
Why Are Virus Infections Like COVID-19 Resistant to Antibiotics?