PHARMACOLOGICAL OPTIONS FOR MANAGEMENT OF COVID-19: ISSUES CONCERNING ETHICS AND RATIONAL MEDICINE USE

PHARMACOLOGICAL OPTIONS FOR MANAGEMENT OF COVID-19: ISSUES CONCERNING ETHICS AND RATIONAL MEDICINE USE

Ravi Rohilla, Parth Kapoor, Nipun Gupta and Harmanjit Singh *

Department of Pharmacology, Government Medical College and Hospital 2, Sector 32, Chandigarh, India.

ABSTRACT: Coronavirus disease 2019 (COVID-19) pandemic has emerged as a major healthcare problem and has posed a great challenge to our existing healthcare facilities. Treatment of COVID-19 has been primarily based on repurposed drugs, drugs approved under emergency authorization or other options which are not thoroughly evaluated in patients with COVID-19, hence, lacking an adequate data on safety and efficacy. Public awareness and education regarding the potential benefits and safety concerns of the available therapeutic/prophylactic options are crucial to avoid ethical and medicolegal issues. Fundraising and global partnership are required to raise the research on potential older drugs likely to be repurposed, along with novel treatment options for COVID-19. A global effort is required to ensure the availability, distribution, and safer administration of COVID-19 vaccines. A rational and ethical approach is required to manage the patients with COVID-19. Equitable access to COVID-19 vaccines should be a priority to end this pandemic. In this review, we have focused on concerns regarding ethics and rational medicine use in view of the available and emerging therapeutic and prophylactic options for the management of COVID-19.

Keywords: Adverse drug reactions, Coronavirus, Cytokine, SARS-CoV-2, Vaccine

INTRODUCTION: On March 2020, the World Health Organization (WHO) announced that there were no safe and effective medicines to cure coronavirus disease-19 (COVID-19) at that time ¹. This led to a significant increase in the search for a cure for COVID-19. The most viable option at that time was off-label prescribing or repurposing of drugs based on preclinical reports or previously found promising in infectious disease ². Off-label drug use does not comply with the definition as advanced by the WHO 1985 for rational use of medicines which stated. "The patient is given right dose of medicine as per clinical requirement for right period of time at an affordable price” ³.

The drug use for indications other than those approved by the national medicines regulatory authority is considered “off-label” use ³. In times of a pandemic like COVID-19, where no effective treatment is available, it is ethical to offer medicine to patient case specific. With so much published literature, it becomes difficult to interpret which drug is to be used in which subtype of patients. So, when drugs are to be administered for a new disease with incomplete evidence, ethical concerns are likely to increase. Letting the patient follow the disease course without giving any available therapies is not justified.

However, at the same time, full autonomy should be given to the patient regarding the acceptance of therapy given and informed about (wherever deemed applicable) the risks associated with the same. Off-label use of drugs is not illegal or irrational, but it is often interpreted wrongly. However, the prescribing physician should take all the responsibility, keep patient safety as the prime concern, and not neglect rare adverse effects, especially when alternative therapy is not available ⁴. It is generally not advisable to accept the clinical research findings before large randomized controlled trials (RCTs) are carried out and their findings are available ⁵. One of the false beliefs among patients and physicians is that the drug certainly has a benefit over harm. Also, too much of optimism about unproven drug such as hydroxychloroquine (HCQ) in the treatment of COVID-19, despite its already known side effects, leads to unethical practice and irrational medicine use ⁶. Off-label use of drugs for treatment of disease not only compromises the safety and efficacy of drug but also gives opportunity to Pharma companies to bypass expensive RCTs and approve the drug for secondary indication ⁷.

In context of Ebola outbreak in 2014, numerous drugs were tested against virus including chloroquine, HCQ, favipiravir, brincidofovir, monoclonal antibodies, antisense RNA, convalescent plasma etc. to rule out an efficacious treatment against Ebola. However, all the efforts were in vain. One of the reasons for this failure was most of the studies did not have control groups ⁵. A similar situation was seen during this pandemic (COVID-19), where most drugs were either started based on in-vitro data or studies carried with single treatment groups. In such situations, ethical issues will arise where there is no clear-cut answer, and one needs to choose a partially correct answer. Further, it is difficult to track whether the four principles of bioethics (beneficence, non-maleficence, respect for autonomy, and justice) are preserved while dealing with the treatment of patients with COVID-19 ⁸. Evolving knowledge regarding the organism and possible therapeutic and preventive strategies demand a balanced approach to justify ethics and rational medicine use. In this review, we will focus on the concerns regarding ethics and rational medicine use linked with treatment of patients with COVID-19.

Current Evidence and Ethical Concerns of Drugs used for COVID-19 Treatment: Off label prescribing of antimalarial drugs such as HCQ and chloroquine was the first hope for the treatment of COVID-19, but later, it was over-hyped politically ^{9, 10}.

This led to the shortage of drugs in the market, depriving the patients of the availability of drugs who were taking drugs for specific indications like rheumatoid arthritis and systemic lupus erythematosus, etc., and encouraging self-medication among asymptomatic patients ¹⁰. Off-label use of antimalarial drugs chloroquine and HCQ has been associated with many controversies ⁹. The United States Food and Drug Administration (US-FDA) issued Emergency Use Authorization (EUA) status to HCQ in March 2020 based on data available then. Still, it later revoked this EUA status based on safety concerns and incomplete trial results ⁹. Further, the HCQ arm of the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, which used high doses of HCQ, was stopped with preliminary results showing possible excess mortality with HCQ (25·7% with HCQ vs 23·5% with usual care).

In addition, HCQ was ineffective in reducing mortality among hospitalized patients due to COVID-19 ¹¹. The WHO-led SOLIDARITY Trial, which included over 12,000 patients in 500 hospitalsites in over 30 countries, for evaluating the efficacy of HCQ, remdesivir, lopinavir/ritonavir, and interferon in severely ill COVID-19 patients, also provided valuable clinical findings compared to standard of care (SOC) ¹². In addition, the current evidence and ethical concerns of drugs used for COVID-19 treatment are presented in Table 1 ^13-45.

TABLE 1: CURRENT EVIDENCE AND POTENTIAL ETHICAL CONCERNS OF DRUGS USED FOR COVID-19 TREATMENT

Extensive Literature and Therapeutic Dilemma: Published literature is extensive and largely differs in opinion. So, results seem inconclusive and make it difficult for physicians to follow any specific form of therapeutic measure. Also, guidelines are changing daily, making the situation and its management more confusing ⁴⁶. In certain situations, misinterpreting results obtained from poorly framed studies or being highlighted by eminent people can be misleading and lead to irrational drug use ⁴⁷. This could be more detrimental in certain developing countries where a stringent regulatory control is lacking. Huge number of research reports or another form of articles are being written on COVID-19 by the academicians/health professionals in different parts of the world. Considering the public emergency, they are being peer reviewed quickly and made available on the web, which is well in the public domain. Quality of the published literature cannot be understood by every person or health professional and many times it could be interpreted in an over-ambitious manner or wrongly ⁴. Every effort should be put in disseminating strong evidence-based data so that the information is not misleading, and the generated data can be helpful in dealing the emergency situations like COVID-19 ⁴.

Potential Ethical Issues: In times of crisis like COVID-19, special attention must be given right from diagnosis to management of infection in pregnant females as they are among the vulnerable group who are more susceptible to infection due to the change in physiological state ⁴⁸. Due care should be given while treating female patients of reproductive age infected with COVID-19. Patient care should be based on a case-to-case basis approach and drugs likely to have fetal adverse effects, for instance, doxycycline and favipiravir, should beavoided ⁴⁸. A medicolegal issue can also arise if person tests COVID-19 positive or his underlying condition deteriorates after stopping the therapy.

It can also lead to an ethical dilemma about which patient should be given corticosteroids or not and who would take responsibility for any untoward incidence if it occurs. In the current scenario, what if you deny such people from taking drug and they become COVID-19 positive. Here also, the ethical concern may arise since principle of beneficence and non-maleficence are compromised. The principle of non-maleficence is violated in this situation. In such scenarios, the undertaking physician is expected to decide the patient’s best interests. However, this may not apply if doctor’s decision contradicts with the patient’s advance directive regarding the therapy use ⁴⁹. Here, a question arises whether doctors should be granted immunity against civil and criminal negligence arising from treatment provided to patients during COVID-19 pandemic? There is a polarization in views on whether to provide criminal negligence immunity to doctors during pandemic ^{50, 51}. From the pandemic's beginning, the efforts of frontline Health Care Workers (HCWs) were well appreciated globally. The HCWs and their families were at a greater risk of developing COVID-19 since they were in close contact with the patients (symptomatic/asymptomatic). Further, such claims from patients regarding the negligence would demotivate the doctors and other healthcare staff, leading to stress and anxiety among them ⁵⁰.

In contrast, negligence claims would improve the standards and help us cope better in future pandemics. Also, the immunity to medical negligence would give a negative impression to the patients regarding their treatment ⁵⁰. If compensation is provided to the COVID-19 patients and their families, it would help to overcome negligence claims liability ⁵⁰.

Informed Consent: In emergency and uncommon situations like infectious disease out-breaks, it is imperative to conduct research as soon as possible and provide feasible treatment options quickly. However, ethical issues, such as valid written informed consent may be needed from every patient while explaining all the pros and cons of such therapies. Informed consent is a process to educate a patient or patient party regarding the purpose, benefits, and potential risks of a medical or surgical intervention and then seek permission before conducting a healthcare intervention ^{52, 53}. It is basically taking a confirmation (signature/thumb impression) from the patient/patient party that they are aware of the health care intervention's possible consequences (risk and benefit). Further, it is the physician’s responsibility to take informed consent from the patient and to assess the patient’s comprehension to take the decision voluntarily regarding acceptance and denial of the medical intervention⁵². However, informing the patient regarding the unavailable treatment option will not provide the information for receiving or refusing the accessible treatment option⁵³. The informed consent can be waived under special circumstances. For instances, public health emergency (pandemic / epidemic), a medical emergency, patient waiver, therapeutic privilege and when patient is incompetent ⁵².

Older and Potential Drugs:

Promising Role? Some older drugs like minocycline and doxycycline, with established safety profiles, strong preclinical evidence, and wide availability, are not being promoted to clinical trials ^{54, 55}. Despite the promising immunomodulatory, anti-viral and anti-inflammatory effects of tetracyclines (minocycline and doxycycline), have not been highlighted much among the potential repurposing drugs against COVID-19 ^{54, 55}. One of the advantages of using these drugs is that they are readily available at an affordable price, even in developing countries ⁵⁵. Further, using minocycline in COVID-19 patients could provide clinical benefits in cytokine-induced myocardial injury and life-threatening acute respiratory distress syndrome (ARDS) ⁵⁵. Purwati et al., reported a significant decrease in viral load within 1 week of treatment of lopinavir/ritonavir plus doxycycline group (n=124) in mild to moderate patients with COVID-19. They also reported that C-reactive protein (CRP) and IL-6 were significantly lower as compared to control groups ⁵⁶.

Another observational study reported that a combination of HCQ and doxycycline showed a promising effect on the treatment of mild to moderate COVID-19 patients. Here, number of patients was less though (n=32); out of which 9 patients also took favipiravir. All patients’ symptoms improved and they tested negative for COVID-19 at the time of discharge (range 8-21 days) ⁵⁷. Yates et al., reported significant improvement in the patients’ symptoms with doxycycline treatment in a case series of four COVID-19 patients with comorbid pulmonary disease. An important thing to note in this study is that all four patients did not administer any other concomitant medication along with doxycycline; their ages ranged from 40 to 88 years ⁵⁴. Also, a drug like budesonide, which is widely available and listed in WHO essential list of medicines ⁵⁸, can be a viable option in the future to treat mild and moderate COVID-19 patients at home and can decrease hospital overload in such emergency situations. Government and other funding authorities should support and encourage research activities so that larger clinical studies can be planned and conducted to reach a meaningful conclusion.

Emergency Vaccine Approval:

Vaccine trial Designs and Approval Issues: Since, the beginning of January 2020, before COVID-19 was declared a pandemic, the race for the vaccine had already begun. Under normal circumstances, it can take more than a decade for vaccine approval (for instance, polio vaccine took nearly 40 years and Ebola vaccine took nearly 5 years) ⁵⁹. Though the WHO took one year to provide the emergency use validation to the first COVID-19 vaccine (i.e., Comirnaty COVID-19 mRNA vaccine) ⁶⁰, many vaccine candidates have already got approval from the regulatory authority and a number of potential vaccine candidates are in phase 1 to phase 3 clinical trials ⁶¹.

Generally, these vaccines have been given emergency approval based on data available from phase I and phase II data on a limited number of subjects. Phase I and phase II trials in the case of vaccines are not enough to give robust data about the efficacy and safety of a vaccine, rather they are more directed towards capturing the information on immunogenicity and reactogenicity ^{62, 63}. In this case, investigators, sponsors, and regulators depend on the extrapolation of data to provide some information on safety and efficacy. Sometimes, it is the post-hoc analysis or analysis with respect to secondary objectives which tells about the likely beneficial effects of a vaccine. There was a transformation of outcomes of vaccine trial from evaluating vaccine efficacy in preventing the COVID-19 in the vaccinated subjects to preventing the disease severity in terms of hospitalizations and deaths ^{64, 65}. This information should be clearly provided to the different stakeholders.

Issues Regarding Public Acceptance of Vaccines and their Availability: Obviously, the vaccine development has marked a sign of relief for the global population, as COVID-19 has not only claimed millions of lives but also brutally affected the global economy. Nearly two dozen COVID-19 vaccines have got authorization, and many more are at different stages of development ⁶¹.

Vaccine hesitancy is defined as the delay in acceptance or refusal of vaccination despite availability of vaccination services. This is influenced by factors such as complacency, convenience, and confidence⁶⁶. A global survey reported that the most common reason for vaccine hesitancy was risk-benefit (scientific evidence e.g., vaccine safety concerns), which accounted for nearly 22 %. Further, vaccine hesitancy (unrelated to the COVID-19 vaccine) was reported in more than 90 % of countries globally ⁶⁷. In June 2020, a global online survey conducted in 19 countries regarding COVID-19 vaccine acceptance ranged from 55% (in Russia) to almost 90% (in China) ⁶⁸. A recently published study reported that the people of low-and middle-income countries (LMICs) have more willingness (mean 80.3%) to take a COVID-19 vaccine as compared to the United States (mean 64.6%) and Russia (mean 30.4%) ⁶⁹.

Even though vaccine acceptance is more in LMICs than developed countries like the United States, the availability of COVID-19 vaccines in LMICs remains a hurdle to end the pandemic. Globally, 38.02 million people are being administered COVID-19 vaccines each day, though only 1.6% of people from low-income countries have received at least one dose ⁷⁰.

The pace at which the vaccination is proceeding in LMICs, it will be around 2023 when the world gets vaccinated.  Thus, the emergence of a highly contagious delta variant remains a threat to a larger unvaccinated population ⁷¹. Even if the vaccination drive has tremendously increased in the past few months, there are still reports of subjects missing the second dose of the vaccine within the stipulated time interval. Currently, India is among the top nations for vaccinating the maximum number of people against COVID-19 ⁷⁰. The incidence of missing second doses remains a concern in some parts of India, which reported nearly 1.3 million doses (Odisha) and 0.394 million doses (Tamil Nadu) ^{72, 73}.

One of the reasons for this was the unavailability of COVID-19 vaccines and overcrowding in vaccination centers⁷³. Missing the second dose of COVID-19 vaccines has also been reported in developed countries like the US. Here, nearly 15 million people missed taking their second dose of vaccine within the ideal window period, which showed an increase from the previous year's missing rate ⁷⁴. Another major ethical issue is that even after vaccination, there is no permanent protection against COVID-19 and its spread. If a patient develops a life-threatening adverse event after vaccination, it can lead to medicolegal issues. Proper history from participants should be taken before vaccinating people. A very important aspect that anyone can miss at a busy vaccine clinic is the possibility of current COVID-19 infection, which is asymptomatic in most cases, and exposure of the subjects to a person who is positive for COVID-19. This demands a robust standard operating procedure (SOPs) before vaccinating people. For instance, every person should be tested for COVID-19 before vaccination; this will ensure that a positive person does not get vaccinated, as the interplay of concomitant COVID-19 infection and vaccine can lead to an exaggerated immune reaction and may lead to excessive cytokine release ⁷⁵. At the same time, if any positive person comes for vaccination, it should be deferred for at least 2 weeks ⁷⁶.

Caution is also important in the case of people who are exposed to COVID-19-positive subjects. In this case, the vaccination may be deferred for a week or so, and after that, COVID-19 testing should be done, and if negative, the vaccine should be given. Reports have been obtained regarding the troublesome adverse effects ⁷⁷of COVID-19 vaccines and they further need to be addressed to avoid ethical and legal glitches. In addition to the above, no specific guidelines are in place to address the issues of medical and financial compensation to be awarded to individuals experiencing serious AEFI (since vaccines are given emergency authorization and are still undergoing late phases of clinical trial). All these issues demand a high level of SOPs and risk evaluation and mitigation plans so that this herculean task could be achieved smoothly.

COVID-19 Vaccines:

The Last Resort to End the Pandemic: COVID-19 vaccines are the last resort to end the pandemic since most drugs failed to show significant benefit to COVID-19 patients. A surge in hospitalization admission has recently been reported in unvaccinated pregnant women. In addition, the women admitted during the delta variant period were found to be at a greater risk than those admitted in the alpha variant period, with a greater proportion having pneumonia ⁷⁸.

A recently published study has shown that the COVID-19 vaccines (BNT162b2 or ChAdOx1 nCoV-19) have a modest difference in effectiveness in the delta variant as compared with the alpha variant after two doses ⁷⁹. Even if someone is fully vaccinated, breakthrough infections are expected since no vaccine is 100% effective. Fully vaccinated individuals are less likely to develop severe illness or get COVID-19 as compared to unvaccinated ⁸⁰. Thus, public awareness is of utmost importance. At the same time, the government and health providers must educate and inform the public regarding the potential benefits of the vaccine and all minor and major safety issues, precautions, and contraindications.

All mild, moderate, and severe adverse events following immunization (AEFI) should be recorded and reported to gain confidence in the vaccine's potential beneficiaries. The stronger the confidence, the larger the population gets vaccinated and fewer cases of severe COVID-19 illness, hospitalization, and death ⁸¹. A global effort is required to ensure the availability, distribution and safer administration of COVID-19 vaccines.

CONCLUSION: In a scenario like the COVID-19 pandemic, choosing off-label drugs becomes more complicated when there is no substantial evidence of their safety and efficacy. Even though off-label prescribing is legal and is practiced in the absence of adequate data but it should also be kept in mind that the clinical evidence in one subject (case specific) may not apply to others. Under normal circumstances and in times of crisis, it is to be noted that the four principles of bioethics (beneficence, non-maleficence, respect for autonomy, and justice) and rational medicine use should always be preserved. Emphasis should be given to promoting research on promising-looking older drugs apart from developing novel therapies. One cannot undermine the role of commercial interests to promote any drug with partial results, creating unnecessary hope among people.

All efforts should be made to provide public education and awareness regarding the risk-benefit profiles of the different therapies so that a rational and shared decision can be made. Over time, the number of COVID-19 cases has decreased, however, the new variant remains a concern for vaccine efficacy. Vaccines are expected to end the pandemic, but vaccine safety, efficacy, availability, and hesitancy among the public are some of the important hurdles. A global effort is required to ensure the availability, distribution, and safer administration of COVID-19 vaccines. Thus, public awareness is of utmost importance, and at the same time it is the duty of the government and healthcare providers to educate and inform the public regarding the potential benefits of the vaccine and all minor and major safety issues, precautions, and contraindications.

ACKNOWLEDGEMENTS: Nil

CONFLICTS OF INTEREST: Nil

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    Rohilla R, Kapoor P, Gupta N and Singh H: Pharmacological options for management of Covid-19: issues concerning ethics and rational medicine use. Int J Pharm Sci & Res 2023; 14(6): 2773-83. doi: 10.13040/IJPSR.0975-8232.14(6).2773-83.

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