COVID-19 and the quest for drugs and vaccines: Statement from the International Society of Drug Bulletins
The COVID-19 pandemic has called for all hands on deck worldwide. Evoking worst-case scenarios such as the Spanish flu of 1918, and the pandemic of the Mexican flu of 2009-2010, people are demanding an effective drug or vaccine. What can and what should they expect?
The Executive Committee of the International Society of Drug Bulletins (ISDB) wants to draw the world’s attention to the quality of drugs and drug trials. ISDB was founded in 1986 with help of the World Health Organization and the European Community with the goal of promoting rational pharmacotherapy.1 Rational pharmacotherapy relates to the prescribing of proper drugs by finding the best balance of efficacy, safety and cost. Properly conducted randomized double-blind trials with a control group on placebo or standard treatment should be the key basis when deciding drug treatment-options for Covid-19.
In early March 2020 the WHO launched SOLIDARITY, a randomized controlled trial comparing four potential drug treatments in multiple countries. Today in the trial registry clinicaltrials.gov more than 200 trials are registered to investigate or are already investigating the effects of interventions and a large number of drugs, some of which are not licensed for sale. Claims of efficacy are sometimes based on theoretical assumptions and in-vitro laboratory tests that do not mirror what the world needs now. Most of the trials have fatal problems with them. Some are observational studies lacking control groups, and others have too few patients, no clear research question, inadequate controls of follow up, incomplete evaluation of adverse effects, or endpoints based solely on laboratory tests.
When drugs enter the market that have not been studied properly and thoroughly, patients can be harmed. We have seen too many examples of this in the recent past like rofecoxib, rosiglitazone, daclizumab, diethylstilbestrol and benfluorex.2-6 These drugs, some of which were meant for everyday complaints and diseases, killed many thousands of patients. It seems that lessons learned from the thalidomide disaster in the sixties are often not applied, forgotten or even abandoned.
The current registration process of new drugs may not protect patients as claims of drug efficacy are often not substantiated by the results of rigorous trials. Even during the Spanish flu which killed many tens of millions of people, some of those deaths were caused by injudicious use of aspirin, at the time virtually the only available drug. It was administered in excessive doses, which some microbiologists claim was responsible for many fatal hemorrhagic pneumonias.7
At the beginning of this century, new antivirals to combat influenza were promoted by manufacturers, and stockpiled by governments around the world on claims they could prevent the spread of the virus even in times of a pandemic. This turned out not to be true, the evidence behind oseltamivir (Tamiflu) showed it shortened the duration of flu symptoms by about 20 hours. Tamiflu’s maker is currently facing a $1.5 billion lawsuit for making misleading statements of the drugs’ effects.8
Despite good intentions and the hope of getting quick access to accelerated drugs and vaccines against the harmful COVID-19 virus, we need to ensure that guiding principles in medicine In dubio abstine (when in doubt abstain from treatment) and Primum non nocere (first, do no harm) aren’t forgotten. An urgent demand for treatments should not lead to inadequate drug evaluations amid the race for a cure by pharmaceutical companies.
Many of our ISDB members have already published articles on the hazards that lie ahead of us if inadequate drug research results lead to harming COVID-19 patients. Our message is clear: randomized trials are the only way to gather quality information about how to treat COVID-19.9 Any experimental use of drugs like chloroquine and hydroxychloroquine should only be used in a proper clinical trial,10 with strict protocols, and data collection.11 If lowering of fever is required use acetaminophen (paracetamol).10 12
ISDB will continue to make our articles freely available to everyone as far as possible.
The Executive Committee of ISDB demands that the entire medical community and health policy decisionmakers act in full awareness of the potential dangers of inadequate drug evaluation.
Politicians and pundits around the world are claiming that hydroxychloroquine and azithromycin taken could be “game changers.” 13 We wish we could share this enthusiasm but we are afraid this could also lead to a large number of people suffering serious side effects and deaths due to the cardiac toxicity of these drugs.14
Everyone wants to see research “change the game” against COVID-19. Any new patients being treated for COVID-19, whenever possible and feasible should be treated as part of a randomized, controlled, cooperative international clinical trial.
On behalf of the commitee of ISDB,
Dick Bijl, Nuria Homedes, Luis Carlos Saiz Fernández, Maria Font, Rita Kessler, Carlos Duran, Alan Cassels
References
1. www.isdbweb.org
2. https://www.drugwatch.com/vioxx/
3. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA2010;304:411-8.
4. Anonymous. The Mediator disaster: So much time wasted, so many lives destroyed. Prescrire Internat 2019;29:303-5.
5. Anonymous. Diethylstilbestrol (DES): also harms the third generation. Prescrire Int 2016;25:294-8.
6. Daclizumab: deaths due to unjustified marketing authorization [editor’s opinion]. Prescrire Internat 2018;27:175.
7. Starko KM. Salicylates and Pandemic Influenza Mortality, 1918–1919 Pharmacology, Pathology, and Historic Evidence. Clin Infect Dis 2009;49:1405–10.
8. https://www.nasdaq.com/press-release/tamiflu-fraud-bilked-%241.5-billion-from-government-alleges-whistleblower-2020-01-13
9. Randomized clinical trials are the only way to learn how we should to treat Covid-19. Therapeutics initiative, special bulletin #2 – March 2020.
10. COVID-19: was ist zum Nutzen von Chloroquin and Hydroxychloroquin bekannt? Arznei-telegramm 25 March 2020.
11. Covid-19 and drug trials: what to make of the initial results? Prescrire Internat March 23 2020.
12. Five don’ts to prevent COVID-19 and death. Med Check 2020;6:3-13.
13. https://www.researchgate.net/publication/340248491_COVID-19_Chloroquine_and_hydroxychloroquine_as_pote ntial_therapies_against_COVID-19
14. Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac complications attributed to chloroquine and hydroxychloroquine± a systematic review of the literature. Drug Saf 2018;41:919-31.