- Informacje o czasopiśmie
- Format
- Czasopismo
- eISSN
- 2084-1264
- Pierwsze wydanie
- 09 Apr 2014
- Częstotliwość wydawania
- 2 razy w roku
- Języki
- Angielski
This paper was written with the support of the Charles University Grant Agency (GAUK) research project no. 910319 “Legal Paradigm of Medical Research: Civil Liability for Death and Bodily Harm”.
In late winter and early spring 2020, the world suddenly found itself facing an unexpected crisis. The novel coronavirus infection, soon named COVID-19,
See, for example, Martin Enserink, ‚Update: ‘A Bit Chaotic:” Christening of New Coronavirus and Its Disease Name Create Confusion’ (12 February 2020) Science < See, for example, Manuel Battegay and others, ‘2019-Novel Coronavirus (2019-nCoV): Estimating the Case Fatality Rate—A Word of Caution’ ( See, for example, Dimple D Rajgor and others, ‘The Many Estimates of the COVID-19 Case Fatality Rate’ (2020) 20(7) The Lancet Infectious Diseases, 776 < See, for example, Anthony Komaroff, ‘The Tragedy of Long COVID’ ( See Helen Branswell, ‘Why “Flattening the Curve’ May Be the World's Best Bet to Slow the Coronavirus’ (11 March 2020) STAT Magazine <
The other pressing question was how to treat COVID-19 most effectively. Some of the first clinical guidelines came from China in early February 2020, providing the first practical advice based on actual clinical experience with the novel disease.
See Ying-Hui Jin and others, ‘A Rapid Advice Guideline for the Diagnosis and Treatment of 2019 Novel Coronavirus (2019-nCoV) Infected Pneumonia (Standard Version)’ (2020) 7(4) Military Medical Research < See Kevin Venus, Laveena Munshi, and Michael Fralick, ‘Prone Positioning for Patients with Hypoxic Respiratory Failure Related to COVID-19’ (2020) 192(47) CMAJ 1532 < See H Hernández Garcés, A Belenguer Muncharaz, and R Zaragoza Crespo, ‘Noninvasive Mechanical Ventilation and COVID-19: Minimizing Dispersion’ (2020) 44(8) Medicina Intensiva 520 <
There was no time to waste by waiting patiently for brand new drugs. Instead, physicians and scientists around the world set on the journey to identify already-existing medicines that could help COVID-19 patients. They would provide them to the patients under the so-called off-label regime, denoting the use of a medicinal product differently than for what it was registered and what is embodied in its Summary of Product Characteristics (SPC). In practice, it most often means that a medicinal product is used for a different indication or a different age group of patients, or that there is altered dosage, dosing frequency, duration of use, etc.
European Commission. Directorate-General for Health and Food Safety, ‘Study on Off-Label Use of Medicinal Products in the European Union’ (9 September 2019) < Vymazal and Šustek (n 10) 263.
This paper will analyse the content and assessment of the standard of care related to the off-label use of medicines in the uncertain and rapidly evolving times of a pandemic. If not explicitly stated otherwise, all the dates relate to the year 2020.
In medical malpractice cases, the breach of duty on behalf of a health professional or health facility usually consists in the failure to comply with the standard of care. It can be basically understood as the standard of the reasonably skilled and experienced doctor or another health worker in a particular professional field.
See Margaret Brazier and Emma Cave, See Brazier and Cave (n 12) 207–209.
We need to look for the answer in a more detailed definition of the standard of care. From its very nature, medicine is a creative enterprise. A skilled doctor does not only follow protocols step by step. She needs to understand how the disease affects the patient's body, the reasons behind the protocol's content, and under what circumstances it might be beneficial or necessary to modify it. Many experts stress that even in a seemingly mechanised medicine, a physician's critical and creative approach is invaluable. Siddhartha Mukherjee makes it clear that ‘human decision making, and, particularly, decision making in the face of uncertain, inaccurate, and imperfect information, remains absolutely vital to the life of medicine (…) the medical revolution will not be algorithmized’.
Siddhartha Mukherjee, Helena Haškovcová, ‘Lege artis v proměnách času [Lege Artis and its Changes over Time]’ in Radek Ptáček, Petr Bartůněk and Jan Mach (eds), Brazier and Cave (n 12) 208.
Using the same cognitive process, physicians are able to proceed even if there are no established protocols or guidelines. Like detectives, they can try to make sense of seemingly unrelated symptoms, deduce their probable causes in the human body's inner functioning, and come up with possible remedies. Apparently, the level of uncertainty in similar situations is high. For this reason, the law does not allow resort to the off-label use of medicines completely freely (arguably except for a patient facing imminent death when a physician could act in the state of necessity).
European law does not explicitly regulate the off-label use of medicines, but there might be applied the regulation of the so-called compassionate use of unregistered medicinal products (especially Article 83 of Regulation 726/2004
Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. < See Vymazal and Šustek (n 10) 263. Vymazal and Šustek (n 10) 263, or Petr Šustek, Tomáš Holčapek, and Martin Šolc, ‘Doporučení pro tzv. off-label použití léčivých přípravků pro pacienty s COVID-19 [Recommendations for the So-Called Off-Label Use of Medicinal Products in COVID-19 Patients]’ (2020) 31(3) Anesteziologie a intenzivní medicína 120. Section 8 (4) of Act No. 378/2007 Coll., on Pharmaceuticals.
On the other hand, no endorsement of public authority is necessary. It might strengthen the argument that the off-label use of a certain medicinal product complies with the standard of care, but it does not automatically secure the legality of such use in all possible cases. Even more importantly, the lack of a public authority endorsement does not mean that the off-label use is not appropriate. While the providers of health services have usually been eager to obtain the official approval to use off-label medicines that might provide hope during the COVID-19 pandemic, it was not strictly necessary to wait for these decisions. Quite the contrary: any drug could have been used off-label as soon as promising results of studies were published that were convincing enough to provide sufficient scientific justification. Another example might be found in the pre-pandemic discussion on the use of gadolinium-based contrast agents in magnetic resonance imaging of the brain. In 2017, the European Commission restricted the registration of several such agents. One of them was the drug marketed as Multihance, the registration of which was limited to the indication of liver imaging. The reason was the discovery of ganolinium deposition in the patients’ brains, even though there have been no known or suspected adverse neurological effects.
See European Medicines Agency, ‘EMA's Final Opinion Confirms Restrictions on Use of Linear Gadolinium Agents in Body Scans’ (19 December 2017) < See Vymazal and Šustek (n 10) 263.
Since the off-label use of medicinal products is a part of clinical practice, all the general requirements for any health service must also be met. Health professionals are obliged to secure the patient's informed consent before interfering with her integrity (or to provide the required information to the patient as soon as possible if she was unable to grant consent at the relevant time); informed consent is, anyway, the legal ground for the provision of health services in the vast majority of cases.
See Josef Salač, ‘Souhlas [Consent]’ in Petr Šustek and Tomáš Holčapek (eds), See Šustek, Holčapek, and Šolc (n 19) 120. Ibid 120.
Definitions of a standard of care in particular jurisdictions usually reflect the uncertain and creative nature of medicine. In the Czech Republic, the standard of care—known by the law as the
There are, therefore, three requirements or aspects that cumulatively form the standard of care:
the objective requirement of the compliance with ‘the rules of science and acknowledged medical procedures’; individualisation on behalf of the patient (‘with the respect to the individuality of the patient’); individualisation on behalf of the health services provider (‘with regard to the particular conditions and objective possibilities’).
For the categorisation of the objective aspect and two individualised aspects of the
The explicit mention of the objective possibilities makes the situation more favourable for the physicians, even though we might argue that even without its embodiment in the legal text, a similar rule would be set by the courts. When doctors have to treat their patients in the absence of reliable evidence, there must be accepted a higher level of uncertainty than under normal conditions. Furthermore, respect for the patient's individuality makes it even clearer that physicians are allowed to be reasonably inventive in finding the most beneficial treatment for each of those they have in care.
Regarding the objective aspect of the standard of care, we must keep in mind that there are no acknowledged medical procedures when a novel disease strikes. Hence, only the criterion of the rules of science remains. It means that physicians need to engage in the above-outlined detective work and use the relevant scientific sources available to make their decisions. In fact, we are facing once again the question of how we can evaluate whether a doctor's actions are sufficiently scientifically justified.
The evaluation of scientific justification for the off-label use of a particular medicinal product in a crisis is, in principle, not very different from the evaluation of compliance with the standard of care under normal circumstances. In both cases, it is necessary to determine whether the relevant procedure is considered medically appropriate by a relevant part of the professional public.
See Petr Šustek, ‘Náležitý odborný postup (lex artis). Obecně [Appropriate Professional Conduct (Lex Artis). General Remarks]’ in Šustek and Holčapek (eds) (n 23) 276.
We will look for this opinion in the same kind of sources as under normal circumstances: in scientific journals, guidelines (if there already are any), textbooks, etc. Nevertheless, the law must reflect that doctors often need to use less specific sources that do not describe the treatment of a particular disease but rather facilitate a deeper understanding of its symptoms and thus help doctors with the innovative process of finding treatment options.
If the sources are specific, they tend to be less reliable during the first months of a new disease. In the COVID-19 pandemic, we have witnessed a massive expansion of preprint papers. The term preprint in the academic context denotes a paper that has been posted on a public server prior to a formal peer review.
See ‘Preprints’ The Lancet <
Preprints have been posted by some of the world's most prestigious medical journals, such as See SSRN, ‘Preprints with The Lancet’ < See ‘Coronavirus (Covid-19)’ New England Journal of Medicine < See Nicholas Fraser and others, ‘Preprinting a Pandemic: The Role of Preprints in the COVID-19 Pandemic’ ( For an analysis of preprints’ reliability and the possibilities for their improvement, see Courtney K Soderberg, Timothy M Errington, and Brian A Nosek, ‘Credibility of Preprints: An Interdisciplinary Survey of Researchers’ (Royal Society Open Science, 28 October 2020) <
In a situation of acute lack of better sources, however, preprints are completely acceptable to scientifically justify a choice of treatment, including the off-label use of medicinal products.
See Šustek, Holčapek, and Šolc (n 19) 121.
As we have shown, the rigour of evaluating scientific sources may be somewhat relaxed in critical situations. In connection with the law's imperative to consider the particular conditions and objective possibilities, the gravity of the crisis provides sufficient grounds for such an approach. It is also necessary to bear in mind that the safety of registered medicinal products, regardless of their original indication, was already proven in sound clinical trials.
Ibid 121.
The tendency to accept almost any serious scientific paper as a source of the standard of care in times of crisis is understandable and, in many cases, beneficial. However, it seems appropriate to balance it with a certain kind of safety check. Otherwise, the safety of the patients, as well as the public trust in health systems, might be compromised. The conditions outlined below were proposed by Šustek, Holčapek, and Šolc in their paper ‘Recommendations for the So-Called Off-Label Use of Medicinal Products in COVID-19 Patients’,
Ibid 119.
A medicinal product should not be used off-label if there is a scientifically based suspicion that it would be harmful to the patient. The scientific justification, but also the suspicion of potential harmful effects, do not necessarily have to originate from experience with the particular drug. It might also be based on the knowledge of or experience with medicines that have the same active substance or are otherwise comparable. Furthermore, a preprint should not establish scientific justification if its results have been subjected to a serious scientific doubt or if an average professional in the field finds them suspicious at first sight.
Ibid 121.
While all these considerations are broad and vague, they might make a crucial difference in navigating the course of action between recklessness and hesitancy in a critical situation. We will illustrate them with a case that seems to be a nearly perfect example of the swift development of science in turbulent times—the rise and fall of hope in hydroxychloroquine (HCQ).
It could have been the medicine everybody was waiting for. When the pandemic first hit European countries in early spring 2020, the promise of HCQ seemed to be great. The medicine has been successfully used for a long time to treat malaria and several autoimmune diseases such as rheumatoid arthritis or lupus.
See American College of Rheumatology, ‘Hydroxychloroquine (Plaquenil)’ (updated April 2020) < See, for example, Jia Liu and others, ‘Hydroxychloroquine, a Less Toxic Derivate of Chloroquine,Is Effective in Inhibiting SARS-CoV-2 Infection in vitro’ (2020) 6(16) Cell Discovery <
Important for spreading the hopes in HCQ was a preprint in the See Philippe Gautret and others, ‘Hydroxychloroquine and Azithromycin As a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial’ (2020) 56(1) International Journal of Antimicrobial Agents 105949 <
The claim of the efficacy of HCQ against COVID-19 was only supported by laboratory experiments and a handful of small clinical studies. Under normal circumstances, the scientific justification of off-label use based on such a limited body of evidence would be at least questionable. However, the situation was anything but normal. The numbers of countries suffering from the pandemic were rapidly increasing, as well as the disease's death toll. Anything that could help patients and save lives was desperately wanted.
Furthermore, HCQ has been a part of clinical practice since the 1950s,
See Drugs.com, ‘Hydroxychloroquine’ (2020) < See Adam Rogers, ‘The Strange and Twisted Tale of Hydroxychloroquine’ (2020) Wired < See Drugs.com (n 40). See Šustek, Holčapek, and Šolc (n 19) 121.
However, doubts started to arise soon. A prime example of these concerns comes from the USA. Late in April, the Food and Drug Administration (FDA) issued a caution against the use of HCQ or a similar drug, chloroquine, for COVID-19 outside of the hospital setting or a clinical trial due to risk of heart rhythm problems. Physicians were recommended to initially evaluate and subsequently monitor patients to whom HCQ was given to identify cardiovascular problems in a timely manner.
See FDA, ‘FDA Drug Safety Communication, Safety Announcement’ (24 April 2020) <
Then, on May 22, a paper in See Mandeep R Mehra and others, ‘Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis’ (2020) The Lancet <
It is not a surprise that the paper became very influential. Published on Friday, it even prompted the World Health Organization (WHO) to halt its Solidarity Trial's HCQ arm on Monday, May 25. With the involvement of thousands of patients, the Solidarity Trial was an important study aiming at discerning which therapies are truly effective and safe for COVID-19 patients. The halting of the HCQ arm consisted in a suspension of new patients’ enrolment until the WHO review had considered available data on the drug.
See Jason Beaubien, ‘WHO Halts Hydroxychloroquine Trial over Safety Concerns’ (NPR, 25 May 2020) < See WHO, ‘“Solidarity” Clinical Trial for COVID-19 Treatments’ (11 August 2021) <
The events in the meantime were probably the most remarkable scientific scandal related to COVID-19 treatments of the year. Just a few days after the publication of the above-outlined Mandeep R. Mehra, Frank Ruschitzka, and Amit N. Patel, ‘Retraction – Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A multinational Registry Analysis’ (2020) 395(10240) The Lancet 1820 <
The data were collected and analysed for the purposes of the paper by the company Surgisphere, which did not agree with transferring the full data set, client contracts, and other necessary data for the third-party analysis. The company claimed that such actions would violate their client agreements and confidentiality requirements. Nevertheless, the reviewers found themselves unable to conduct an independent and private peer review and therefore were withdrawn from the peer-review process. In reaction to that, the paper's coauthors themselves (with the exception of the co-author who owned Surgisphere) requested its retraction.
Ibid. Characteristically for the COVID-19-related scientific communication, which has been largely taking place on social networks, we might cite here
Nevertheless, these events were no victory for the proponents of HCQ COVID-19 treatment. According to the later studies, HCQ is not significantly dangerous but also not beneficial for patients with COVID-19.
See, for example, Michael S Saag, ‘Misguided Use of Hydroxychloroquine for COVID-19: The Infusion of Politics into Science’ (2020) 324(21) JAMA 2161 < See Berkeley Lovelace Jr. and Kevin Breuninger, ‘Trump Says He Takes Hydroxychloroquine to Prevent Coronavirus Infection Even Though It's an Unproven Treatment’ (CNBC, 18 May 2020) < See FDA, ‘FDA Drug Safety Communication, Safety Announcement’ (24 April 2020) (n 44). See Rogers (n 41). See, for example, BBC, ‘Coronavirus: Hydroxychloroquine Ineffective Says Fauci’ (29 July 2020) < For a brief timeline, see Libby Cathey, ‘Timeline: Tracking Trump Alongside Scientific Developments on Hydroxychloroquine’ (ABC News, 8 August 2020) <
The development of scientific justification of the off-label use of HCQ for COVID-19 can be roughly summarised as follows:
In 2020, several other medicines registered for different indications were, at least for some time, seen as promising for COVID-19 treatment. For example, some studies suggest that an antiviral drug, favipiravir, shortens hospitalisation stays and fastens the alleviation of symptoms,
See, for example, Andrey A Ivashchenko and others, ‘AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial’ (2020) 73(3) Clinical Infectious Diseases < See, for example, Ping-Jen Chen, Chien-Ming Chao, and Chih-Cheng Lai, ‘Clinical Efficacy and Safety of Favipiravir in the Treatment of COVID-19 Patients’ (2020) 82(5) Journal of Infection < See FDA, ‘FDA Approves First Treatment for COVID-19’ (22 October 2020) < See WHO, ‘WHO Recommends against the Use of Remdesivir in COVID-19 Patients’ (20 November 2020) <
On the other hand, dexamethasone, a cheap corticosteroid commonly used for many indications,
See Electronic Medicines Compendium, ‘Dexamethasone 2mg Tablets’ (updated 19 May 2022) < See, for example, The RECOVERY Collaborative Group, ‘Dexamethasone in Hospitalized Patients with Covid-19’ (2021) 384(8) New England Journal of Medicine 693 < See EMA, ‘EMA Endorses Use of Dexamethasone in COVID-19 Patients on Oxygen or Mechanical Ventilation’ (18 September 2020) < See, for example, Electronic Medicines Compendium, ‘Dexamethasone 3.3mg/ml Solution for Injection’ (updated 20 February 2020) <
As of February 2021, there have been several other medicines used off-label against COVID-19. For example, trials suggest the efficacy of a rheumatoid arthritis drug tocilizumab and other interleukin-6 inhibitors,
See The RECOVERY Collaborative Group, ‘Tocilizumab in Patients Admitted to Hospital with COVID-19 (RECOVERY): Preliminary Results of a Randomised, Controlled, Open-Label, Platform Trial’ ( See Maria Isabel Lopes and others, ‘Beneficial Effects of Colchicine for Moderate to Severe COVID-19: A Randomised, Double-Blinded, Placebo-Controlled Clinical Trial’ (2021) RMD Open 7 < Sanjay Ramakrishnan and others, ‘Inhaled Budesonide in the Treatment of Early COVID-19 Illness: A Randomised Controlled Trial’ (
Moreover, specific COVID-19 treatments—monoclonal antibodies such as bamlanivimab or their cocktails such as Regeneron's REGN_COV2—have been tested for their efficacy in patients who do not yet need hospitalisation.
See, for example, Robert L Gottlieb and others, ‘Effect of Bamlanivimab as Monotherapy or in Combination with Etesevimab on Viral Load in Patients with Mild to Moderate COVID-19: A Randomized Clinical Trial’ (2021) 325(7) JAMA 632 < See FDA, ‘Coronavirus (COVID-19) Update: FDA Authorizes Monoclonal Antibodies for Treatment of COVID-19’ (21 November 2020) < See EMA, ‘EMA Reviewing Data on Monoclonal Antibody Use for COVID-19’ (2 April 2021) <
The off-label use of medicinal products is a standard part of medical practice. If it meets certain criteria, it is not contradictory to the standard of care. According to one of these criteria, the off-label use of medicinal products requires scientific justification. The standard of scientific evidence required for justification can be lowered in a critical situation. That has also been the case in the COVID-19 pandemic, especially in its early months. Even preprints can be used for scientific justification if the results have not been relevantly scientifically questioned. The case of HCQ is a vivid illustration of scientific justification of the off-label use amid a pandemic, with the necessary reliance on very small studies and
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