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6Трансформация клинических исследований, вызванная COVID-19: биоэтические и методологические аспекты
Нартова Мария Андреевна,
аспирант, кафедра философии и методологии науки МГУ имени М.В. Ломоносова E-mail: m.nartova@mail.ru
Пандемия COVID-19 стала настоящим вызовом для медицинского сообщества, резко отделив привычную практику от принимаемых новых решений и буквально переписала методологическую и биоэтическую историю современной медицины. В статье предлагается проанализировать эту трансформацию и предпринять попытку постановки проблемных с биоэтической и методологической точек зрения вопросов на примере клинических исследований. Статья содержит хронологическое описание процесса становления клинических исследований как одного из методов доказательной медицины с древнейших времен и до ^VID-^, а также включает в себя описание основных методологических решений индустрии клинических исследований в ответ на пандемию на примере России, США и ЕС. Показано, что предложенные модификации методологии проведения клинических исследований оказались унифицированы в разных странах, а сфера клинических исследований показала высокую степень адаптивности к форс-мажорным ситуациям. Основной трансформацией стал удаленный формат взаимодействия между участниками исследований, в том числе путем внедрения IT-решений. Однако, пандемия ^VID-19 и внедренные модификации актуализировали ряд проблемных вопросов, требующих дальнейшей дискуссии в научном сообществе.
Ключевые слова: биоэтика, клинические исследования, пандемия, общественное здоровье и здравоохранение, история медицины.
Introduction
Since ancient times, health has been ^nsidered to be the most important value for both the individual person and humanity. On the contrary, an illness, especially a severe one, was a duel in which, due to historical and sociocultural aspects, the patient was often doomed to lose. Many diagnoses that became routine for a modern patient meant imminent death until the 20th century, and that is why the profession of a doctor seems to include more ethical, psychological, compassionate and supportive characteristics rather than a qualitative potential in matters of therapy. The idea that it is necessary to check if any medical drug is efficient and safe before its usage through clinical trials is obvious for modern society, but in fact this approach is relatively new. The first randomized controlled clinical trial was reported only in 1948 and for more than half a century dinical research was ^nsidered to be a stable area of evidence-based medicine, meeting most of the bioethical and methodological challenges of our time. The situation has dramatically changed due to the COVID-19 pandemic identified in China in the late 2019. Professional society all over the world had to decide whether it is possible to continue conducting clinical trials, and if so, how should we act to make it safe for those who take part in it. This became both an ethical and methodological dilemma with the need to make decisions in real time. Before examining the changes that led to a new step in clinical trials due to COVID-19, let us briefly review the history of pharmacology and clinical trials with an aim of better understanding causal relationships and logical basics in practice of medicine.
Ancient times
The ancient approach in medicine could be mostly described as a period of mythology and belief. Ancient Greek, India, China and other civilizations had a kind of pharmacological legacy with proposed treatment options, but this period could be hardly determined as an evidence-based stage of medicine because of a few reasons. First of all, it was a lack of knowledge in medicine and related disciplines such as biology and chemistry. During this period there has not been developed any knowledge base describing the real nature and mechanism of development of any disease (pathogenesis). Most explanations were based on guesswork and mythological foundations, which stays in line with explained the lack of scientifically based medical knowledge. Some civilizations prohibited dissection and more often it was only imagination that helped to suppose a structure of the human body. Chinese doctors have considered the yin and yang disbalance to be an origin of illness, ancient Indian concept among other things, noted adverse health effects of spoiled water, the effects of wind and unfavorable terrain with no details explaining such considerations from physiological or biochemical points of view [1]. It should be also borne in mind that the occurrence of disease was explained by mystical and religious principles very often. Despite that fact, ancient times saw an important step made for the development of medicine in this question by the ancient Greek philosopher and doctor Hippocrates, who doubted the divine cause of epilepsy in his work «On the sacred disease» [2]. To sum up, this period could be probably
described in the words of Hippocrates: "The best doctor seems to me the one who has the gift of foresight'. Indeed, with lack of a medical knowledge base, foresight could become a very important skill for ancient doctors.
Middle ages and Renaissance
The importance of empirical principles including the increase of knowledge base in medicine started to become more evident in the Renaissance. Particulary, Paracelsus (1493-1541) has offered the thesis "experience is the theory of doctor' as well as an explanation of how the same substance could be used as a medicine and as a poison depending on its dosage. It became an important thesis with the help of which one could describe the non-efficacy of some treatments exactly because of the incorrect dosage used. Nevertheless, this period knew lots of ineffective and even dangerous substances which were considered to have a certain pharmacological activity. Unfortunately, neither methodology nor the theoretical basics of medicine could resolve the problem of insufficient and other dangerous and painful treatments, which may rightly seem terrible and inhumane. Fortunately, sometimes medical findings occurred even without an evidence-based approach.
For example, it was only the lack of standard therapy (boiling oil) which obliged French surgeon Ambroise Par (1510-1590) to develop a new mixture for wound cleaning. The newly developed therapy turned out to be less painful and more effective than the standard and well-known therapy of wound treatment with boiling oil. Nowadays, taking into account the bioethical principles of medical care it is extremely difficult even to imagine that such a painful therapy remains common for years with no attempts to find out the better way of treatment [3]. With Ambroise Pare's forced experiment we could see one of the first comparative cases with two or more groups of patients divided by a different approach in treatment. Despite the modern methodology of clinical trials being markedly unlike what was done by Pare, this comparative principle remains a very important part of biomedical research.
The first planned comparative study was performed by the British Navy physician James Lind, who confirmed the therapeutic effect of lemon juice to prevent and to treat scurvy and laid down a foundation for future clinical trials [4]. He divided 12 sailors into 6 groups and prescribed one certain treatment to each group. Remarkably, he knew nothing about the scurvy pathogenesis as well as the vitamin C existence, but somehow was able to determine both the correct methodology of experiment and the substances (including lemon juice effective against scurvy) to be examined. Bioethical foundations of modern medicine are extremely strict about prescribing substances with unknown effects for experimental purposes, but just a few centuries ago it was often limited only by the imagination of a doctor. For example, along with lemon juice, Lind tested the effectiveness of sea water, vinegar, sulfuric acid and even cider.
The XX century: a turning point
Step by step, the importance of scientific research in medicine became more and more obvious, but the first serious progress in the development of clinical research methodology came only in the middle of the 20th century, when the British Medical Research Council conducted the first randomized placebo-controlled trial of streptomycin for the treatment of pul« monary tuberculosis with controlled and experimental groups " of patients enrolled [5]. This was big progress made by British S3 scientists in the field of clinical trials if compared with previous ~ examinations of substances considered to have pharmaco-¡1 logical activity. So it took almost two centuries from Lind's
experiment to formulate and to put into practice the major principles of biomedical research of medical drugs. There have been 4 important methodological solutions implemented, which allows us to consider this UK streptomycin study as a very important step in evidence-based medicine. According to Sackett, the practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research [6]. The streptomycin study includes a special approach in randomization (to indicate whether a patient will take the study drug or the placebo), the careful patients' enrollment into the study, a meticulous study documentation and methodological reflection carried out along with an ethical committee after the end of the study.
The middle of XX century became a turning point for clinical trials not only from methodological, but also from a bioethical point of view. The Nazi doctors' inhumane and cruel actions during the Second World War became an occasion for deep reflection in matters relating to biomedical research in humans and caused development of one of the most important ethical documents - The Nuremberg Code [7]. The Code includes 10 basic bioethical rules of how to perform biomedical experiments in humans, including the necessity to obtain informed consent from a potential patient prior to any research and possibility to quit from the research any time upon the patient's decision. It was also postulated that biomedical research should benefit the society with no alternative options to confirm the drug's safety and efficacy except by human's participation in it. Afterwards there have been other important documents implemented in order to describe the ethical and methodological basics of biomedical experiments, for example The Declaration of Helsinki (1964), The Belmont Report (1976), The Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine (1997).
Despite methodological and bioethical principles implemented, medical society faced serious challenges in attempts to achieve transparency of clinical trials and to maximize drug safety. The Thalidomide tragedy showed that preclinical studies conducted in animals cannot guarantee 100% safety for a human. One of the most famous cases confirming this thesis is the history of prescribing a sedative drug - thalidomide. Being efficient and safe for most people at first glance, thalidomide turned out to be extremely dangerous for pregnant women increasing infant mortality and leading to embryopathy [8]. It took years and thousands of victims to understand that the increasing number of disabled children is not an accident, but it is mostly considered as an accidental occurrence with no intentional prescriptions in order to harm women or a baby. Unfortunately, some inhumane methods were implemented intentionally. The Tuskegee Study of Untreated Syphilis in the Negro Male (1932-1972) became an example of ethnic discrimination, nontransparent and unfair behavior of doctors, who did not provide existing treatment to patients because of examining how the disease develops in their body [9]. This has confirmed the idea of necessity for constant rigorous ethical and regulatory supervision, which has been successfully implemented in most countries conducting clinical trials.
Following the development of clinical trials area implied some methodological and bioethical updates, but the basics remains constant. The design of trials should be logical and transparent, the use of placebo should be ethically justified, all involved patients should be legally and ethically protected by informed consent form approved by ethical committees. With all local and international requirements and guidelines, the established practice of clinical trials seemed to be well-regulated and properly realized. This has changed dramatically due to the COVID-19 pandemic, which laid bare many controversial and imperfect aspects of clinical trials
both from methodological and bioethical points of view [10]. It is proposed to consider the main ethical complexities that were made during the pandemic.
COVID-19: new challenges
With the aim to decrease the speed of COVID-19 virus spread, most countries decided to announce a lock-down. With face-to-face meetings, on-site drug delivery, patients' visits to hospitals, this affected clinical trials a lot. Specialists were faced with an ethical dilemma because of the necessity to choose whether it is possible to continue to conduct clinical trials with the risk of being infected by COVID-19 during visits to hospitals or whether there was a need to pause trials and keep patients safe with no access to study drugs and diagnostic procedures. Hospitals claimed the lack of human and non-human resources due to the load of intensive care units, patients were unable to visit hospitals in frames as expected by trial's schedule timeframes and the supply chain issues interfered with the delivery of biosamples and drugs. In order to prevent the total disruption of the clinical trials area, the regulatory authorities have issued recommendations on how to act within the pandemic in order to ensure patients' safety. In Russia the recommendations on how to conduct clinical trials during COVID-19 were announced by the Ministry of Healthcare at the end of March 2020 [11].
The main recommendations were:
- Usage of alternative methods of communication, preferably distant ones (e.g. telephone contact instead of a face-to-face visit to a medical center)
- Implementation of alternative ways of drug delivery and biosamples collection (e.g. delivery of investigational drug to patient at home, collection of biological material from patients at home)
- Ensuring the flexibility of ethics committees and other involved parties, if any;
The similar recommendations announced by the Food and Drug Administration (USA) [12] and European Medicines Agency (EU) [13] showed the unified international response of medical society to the pandemic. For sure, there have been some local requirements on how to act with COVID-19, but major implemented steps remain alike and demonstrate the unified approach of medical and scientific society.
At the same time, the COVID-19 pandemic not only showed a flexibility of clinical trials, but raised a number of questions to be discussed. Could this situation be predicted at least from a methodological aspect? Digital technologies were a very important part of our lives, but before COVID-19 we saw a very moderate digitizing of clinical trials [14]. Was it right? Are there any negative aspects of such digitizing? Can we somehow prioritize studies or patients in lack of resources [15]? Professional society is now aimed at discussing such controversial questions. Conclusion
The COVID-19 has become a real challenge for the clinical trials area and caused fundamental modifications in its methodology. Obviously, the scientific community will be comprehending the experience of the pandemic for a long time to come. Time will tell how reasonable and justified these decisions were. It seems that despite the significant progress achieved, methodology of clinical trials as well as its bioethical basics still could be and most probably should be improved.
Литература
1. Zabludovskii P.E., Kriuchok G.R., Kuzmin M.K., Lev-it M.M. (1981) The history of medicine, Moscow, Medicine publishing house, 352 p.
2. Hippocrates. (1936). Selected books, Moscow, State Publishing House of Biological and Medical Literature. 736 p.
3. Skliarova E.K., Zharov L.V., Dergousova T.G., (2016) The history of pharmacia: Scientific magazine. Rostov-on-Don, Fenix, 238 p.
4. Jenkins, J., & Hubbard, S. (1991). History of clinical trials, In Seminars in oncology nursing. 228-234. DOI: 10.1016/0749-2081(91)90060-3
5. A Medical Research Council Investigation. (1950). Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid, The British Medical Journal. 1073-1085.
6. Sackett D.L., Rosenberg W.C., Gray M.J., Haynes R.B., Richardson W.S.(1996). Evidence based medicine: what it is and what it isn't, Bmj.71-72. DOI: 10.1136/ bmj.312.7023.71
7. Iudin, B.G. (1998). Ethics of biomedical experiment. In Bioethics: principles, rules, problems. Moscow, Editorial UPCC, 472 p.
8. Kim J.H., Scialli A.R. Thalidomide: the tragedy of birth defects and the effective treatment of disease //Toxico-logical sciences. - 2011. - T. 122. - № . 1. - C. 1-6. DOI: 10.1093/toxsci/kfr088
9. Alsan M., Wanamaker M., Hardeman R.R. The Tuske-gee study of untreated syphilis: A case study in peripheral trauma with implications for health professionals // Journal of general internal medicine. - 2020. - T. 35. -C. 322-325. DOI: 10.1007/s11606-019-05309-8
10. Ledford, H. (2021). The COVID pandemic's lingering impact on clinical trials, Nature, 341-342.
11. Ministry of Healthcare of Russian Federation (2020). On the conduct of clinical trials of drugs in the context of the COVID-19 coronavirus pandemic. Available at: https://minzdrav.gov.ru/ministry/61/11/po-voprosam-provedeniya-klinicheskih- ¡ ssledovaniy-lekarstvennyh-preparatov-v-usloviyah-pandemii-koronavirusa-covid-19 (accessed 16 February 2023).
12. Food and Drug Administration (2020). Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, and Institutional Review Boards. Available at: https://www.fda.gov/media/136238/download (accessed 16 February 2023).
13. European Medical Agency (2020). Guidance on how to manage clinical trials during the COVID-19 pandemic (v3, 28 April 2020). Available at: https://health.ec.eu-ropa.eu/system/files/2020-05/guidanceclinicaltrials_ covid19_pres_en_0.pdf (accessed 16 February 2023).
14. van Dorn A. (2020). COVID-19 and readjusting clinical trials, The Lancet, T. 396. № .10250, 523-524. DOI: 10.1016/S0140-6736(20)31787-6
15. Palazzani L. The pandemic and the ethical dilemma of limited resources: Who to treat? //Bioethics Update. -2020. - T. 6. - № . 2. - C. 67-79. DOI: 10.1016/j. bioet.2020.09.003
TRANSFORMATION OF CLINICAL TRIALS CAUSED BY COVID-19: BIOETHICAL AND METHODOLOGICAL ASPECTS
Nartova M.A.
Lomonosov Moscow State University
The COVID-19 pandemic being a real challenge for the medical society makes a sharp distinction between the usual practice and the newly implemented solutions and literally rewrites the methodological and bioethical history of modern medicine. The article proposes to analyze this transformation from bioethical and methodological points of view on the example of clinical trials. The article contains a chronological description of clinical trials becoming a part of the
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evidence-based medicine starting from the ancient times and until COVID-19 pandemic, and also includes a description of the main methodological solutions in clinical trials in response to the pandemic in Russia, the USA and EU. It is shown that the proposed modifications of the methodology of clinical trials conduction turned out to be unified in different countries, and the clinical trials area has shown a high flexibility to force majeure cases. The main transformation was the remote way of interaction between participants including the implementation of IT solutions. The COVID-19 pandemic and implemented solutions actualized, however, a number of problematic issues from methodological and bioethical points of view that require further discussions in the scientific community.
Keywords: bioethics, clinical trials, pandemic, public health, history of medicine.
References
1. Zabludovskii P.E., Kriuchok G.R., Kuzmin M.K., Levit M.M. (1981) The history of medicine, Moscow, Medicine publishing house, 352 p.
2. Hippocrates. (1936). Selected books, Moscow, State Publishing House of Biological and Medical Literature. 736 p.
3. Skliarova E.K., Zharov L.V., Dergousova T.G., (2016) The history of pharmacia: Scientific magazine. Rostov-on-Don, Fenix, 238 p.
4. Jenkins, J., & Hubbard, S. (1991). History of clinical trials, In Seminars in oncology nursing. 228-234. DOI: 10.1016/0749-2081(91)90060-3
5. A Medical Research Council Investigation. (1950). Treatment of pulmonary tuberculosis with streptomycin and para-amino-salicylic acid, The British Medical Journal. 1073-1085.
6. Sackett D.L., Rosenberg W.C., Gray M.J., Haynes R.B., Richardson W.S.(1996). Evidence based medicine: what it is and what it isn't, Bmj.71-72. DOI: 10.1136/bmj.312.7023.71
7. ludin, B.G. (1998). Ethics of biomedical experiment. In Bioethics: principles, rules, problems. Moscow, Editorial UPCC, 472 p.
8. Kim J. H., Scialli A.R. Thalidomide: the tragedy of birth defects and the effective treatment of disease //Toxicological sciences. - 2011. - T. 122. - № . 1. - C. 1-6. DOI: 10.1093/toxsci/ kfr088
9. Alsan M., Wanamaker M., Hardeman R.R. The Tuskegee study of untreated syphilis: A case study in peripheral trauma with implications for health professionals //Journal of general internal medicine. - 2020. - T. 35. - C. 322-325. DOI: 10.1007/s11606-019-05309-8
10. Ledford, H. (2021). The COVID pandemic's lingering impact on clinical trials, Nature, 341-342.
11. Ministry of Healthcare of Russian Federation (2020). On the conduct of clinical trials of drugs in the context of the COV-ID-19 coronavirus pandemic. Available at: https://minzdrav. gov.ru/ministry/61/11/po-voprosam-provedeniya-klinicheskih-issledovaniy-lekarstvennyh-preparatov-v-usloviyah-pandemii-koronavirusa-covid-19 (accessed 16 February 2023).
12. Food and Drug Administration (2020). Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency. Guidance for Industry, Investigators, and Institutional Review Boards. Available at: https://www.fda.gov/media/136238/ download (accessed 16 February 2023).
13. European Medical Agency (2020). Guidance on how to manage clinical trials during the COVID-19 pandemic (v3, 28 April 2020). Available at: https://health.ec.europa.eu/system/files/2020-05/ guidanceclinicaltrials_covid19_pres_en_0.pdf (accessed 16 February 2023).
14. van Dorn A. (2020). COVID-19 and readjusting clinical trials, The Lancet, T. 396. № .10250, 523-524. DOI: 10.1016/S0140-6736(20)31787-6
15. Palazzani L. The pandemic and the ethical dilemma of limited resources: Who to treat? //Bioethics Update. - 2020. - T. 6. -№ . 2. - C. 67-79. DOI: 10.1016/j.bioet.2020.09.003
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