Remdesivir emergency approvals: a comparison of the U.S., Japanese, and EU systems

ABSTRACT

Introduction

There were no formal regulatory approvals for antivirals for the COVID-19 pandemic as of June 2020.

Areas covered

We compare the first regulatory approvals for remdesivir, through emergency pathways available to three of the main regulators in the world, the U.S., Japan, and the EU. We look at the data supporting the decisions and how authorities exchanged information and collaborated to speed up approvals.

Based only on topline data available as of 29 April 2020, regulators granted approvals to remdesivir based on very limited but robust data and waiting for more safety and efficacy data. This included the Emergency Use Authorization in the U.S. on 1 May, the Special Approval for Emergency in Japan on 7 May, and Compassionate Use (3 April) followed by a Conditional Marketing Authorization in Europe (Opinion 25th June, Decision (3 July)).

Expert opinion

While the regulatory approvals were clearly based on evidence, regulators used agile methods to speed up approval, and make the first antiviral with reliable data available to patients in their constituencies in a very short time frame. More data and wider patient access are still necessary for this product, and more treatments are needed for patients affected by COVID-19.

KEYWORDS:

• Regulatory
• emergency use
• COVID-19
• anti-viral
• marketing authorization
• compassionate use
• conditional marketing authorization

1. Introduction

There was in September 2020, no formal regulatory approval for either a medicine or a vaccine for COVID-19, the pandemic due to SARS-Cov2, which began in Wuhan Province, China, in December 2019. As the pandemic grew, regulators across the world [1] indicated they would apply regulatory flexibility or agility and speed up regulatory processes once evidence of a potentially effective treatment was available to them.

Within a few months over a thousand clinical trials of potential treatments were launched [2]. By 29 April 2020, data from two completed trials and interim data from a third large trial were made available to regulators, in support of the use of remdesivir in patients with COVID-19. Within a highly compressed timeline, regulatory authorities reviewed the data and used their respective regulatory frameworks for early access. Here we present an overview of three major regulatory agencies’ approaches and collaboration for making the drug remdesivir available to clinicians in a widespread emergency setting.

2. Data summary

On 29 April 2020, the Data Safety Monitoring Board released interim data from a large clinical trial led by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) studying remdesivir in seriously ill, hospitalized patients (NCT04280705). This randomized, double-blind, placebo-controlled trial involved 1063 patients from 68 sites, 47 in the United States, and 21 in countries in Europe and Asia [3]. Patients who were treated with remdesivir showed a 31% faster time to recovery than those who received placebo (p < 0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p = 0.059). These data were made available in the topline summary form (Table 1) and to many regulators around the world. FDA worked closely with NIH to assure, to the extent possible, the reliability of their data, the key driver in making an assessment of whether widespread access to the drug might be warranted outside of clinical trials.

Table 1. Remdesivir topline results (extract) – NIAID trial [3]

	Overall
	Remdesivir (n = 538)	Placebo (n = 521)
Number of recoveries	334	273
Days to recovery Median (95%CI)	11 (9–12)	15 (13–19)
Recovery ratio (95% CI) p value	1.32 (1.12–1.55) P < 0.001
Mortality
Hazard ratio (95% CI)	0.70 (0.47–1.04)
N deaths until D14	32	54
Kaplan Meier estimate (95% CI)	7.1% 5–9.9	11.9% 9.1–15.4

The positive NIAID data came after two previous clinical trials showing inconclusive results: the SIMPLE trial led by Gilead in 155 sites in 8 countries, was a randomized, open-label trial in 401 hospitalized, severely ill patients with severe COVID-19 comparing 5 days versus 10 days of treatment (Table 2). Its results were, importantly, similar to whether patients received 5 or 10 days of treatment [4]. The third set of data came from a randomized placebo-controlled trial, performed by Gilead in China, which had been terminated due to lack of enrollment as the pandemic subsided in that country, and was thus underpowered (237 patients randomized 2:1 to remdesivir or placebo, instead of 453 needed to be enrolled) (Table 3). The patient population was similar to that of the SIMPLE trial, except for the allowed use of steroids, and patients were randomized to 5 or 10 days of treatment with remdesivir compared to standard of care. Data in 237 patients showed that remdesivir use was not associated with a significant difference in time to clinical improvement [5].

Table 2. Remdesivir topline results (extract) – SIMPLE trial [4]

	Overall
	Remdesivir 5 days (n = 200)	Remdesivir 10 days (n = 197)
Time to recovery (median day of 50% cumulative incidence	10	11
Mortality at D14 (%)	16 (8)	21 (11)

Table 3. Remdesivir topline results (extract) – Chinese trial [5]

	Overall
	Remdesivir (n = 158)	Placebo (n = 78)
Time to clinical improvement (95%CI)	21 13–28	23 15–28
Hazard ratio	1 · 23 [95% CI 0 · 87–1 · 75).
Mortality at D28 (%)	22 (14%)	10 (13%)

On the basis of these data and despite not having access to the full set of audited data, regulators were called to decide whether and how to employ their available emergency procedures to allow patient access to remdesivir in the setting of the pandemic.

Later on, more data, including the final NIAID trial report [6] and further publications became available to regulators and health-care professionals. They are not included here as they were not part of the early regulatory reviews and could not support the decisions made at the time.

Many countries have a model or scheme, based on their own legal framework, to allow rapid access to medicines in emergency situations. We present here the frameworks in the United States, Japan, and the EU outlined in Table 4, followed by how these were applied to remdesivir (Table 5) in extensive collaboration.

Table 4. Comparison of legal frameworks in the U.S.A., Japan, and the European Union

	U.S.A. Emergency Use Authorization	JAPAN Special Approval	European Union Compassionate Use Opinion (EMACHMP)	European Union Conditional Marketing Authorization
Objective	Protection of the nation’s public health against Chemical, Biological, Radiological and Nuclear threats by facilitating the use and availability of Medical Counter Measures..	Prevent spread of diseases that may seriously affect the lives and health of people and spread of other health hazards.	A treatment option that allows the use of an unauthorized medicine. Under strict conditions, products in development can be made available to groups of patients in the European Union suffering from life-threatening, long-lasting or seriously debilitating illnesses, which cannot be treated satisfactorily with any currently authorized medicine and who cannot enter a clinical trial.	Benefit to public health of the medicinal product’s immediate availability on the market outweighs the risk of having less comprehensive data available.
Legal basis	Section 564 of the Federal Food, Drug and Cosmetic Act (the Act) (21 U.S.C. 360bbb-3)	14–3 of the Pharmaceuticals and Medical Devices Act	Art 83 of Reg (EC) No 726/2004	Com Reg (EC) No 507/2006
Requirements	Declaration by the Secretary of HHS of a public health emergency that justifies the emergency use of Medical Counter Measures (e.g. drug, vaccine, antidote or diagnostic)	1) an emergency situation requires the use of an unapproved medical product to prevent damage to public health caused by the spread of diseases, and 2) such product is legally available in a country with a regulatory system for medical products that is equivalent to Japan.	The medicinal product concerned must either be the subject of an application for a marketing authorization (…) or must be undergoing clinical trials.	All following requirements: - the benefit-risk balance of the product is positive; - it is likely that the applicant will be able to provide comprehensive data; - unmet medical needs will be fulfilled; - the benefit to public health of the medicinal product’s immediate availability on the market outweighs the risks due to the need for further data
Approved alternatives	No approved alternative	No proper method is available	No satisfactory alternative therapy No possibility to enter a clinical trial	Unmet medical needs
Duration	No specific duration limit		Updates of CHMP opinions may be requested by MS(s) or initiated by the Committee based on data provided by MS(s) or companies	Valid for 1 year Renewable
Patient (or surrogate) consent required?	No.	Informed consent due to Special Approval	Consent	Not required
Pharmacovigilance measures	Reporting of ADRs to FDA MedWatch directly or company. Company reports to FDA	To submit ICSRs to MHLW/PMDA To develop and implement RMP	Safety conditions as part of the opinion, including safety reporting RMP to be provided by Opinion Holder	RMP and usual safety reporting. Specific Obligations may include Post Approval Efficacy and/or Safety Studies
Product Distribution	U.S. Government distributes to states based on status of the pandemic and need in regions	To report names of clinical institutes where Special Approval Holder delivers the product, and quantities	Possible restriction of prescriptions Distribution controlled by Opinion Holder	Possible restriction of prescriptions Distribution controlled by MAH
End of temporary measures	The EUA ends when the Secretary determines that the circumstances justifying the EUA no longer exist or when there is a change in the approval status of the product such that an EUA is no longer needed.	When emergency conditions no longer persist, or the withdrawal is necessary to prevent damage to public health.	Not specified, but after information about authorized medicines is published on the EMA website	Yearly review. May be modified or withdrawn based on new data. When all Specific Obligations fulfilled and assessed positively, transformed into normal Marketing Authorization

ADR: Adverse Drug Reaction; ICSR: Individual Case Safety Report; MAH: Marketing Authorization Holder; RMP: Risk Management Plan

Table 5. Comparison of schemes for remdesivir

	U.S. Emergency Use Authorization	JAPAN Special Approval	COMPASSIONATE USE (EU)	Conditional MA (EU)
Date	1 May 2020	7 May 2020	CHMP opinion 2 April 2020 Update 11 May 2020	Submission 5 June and positive Opinion on 25 June 2020.
Indication	Treatment of suspected or laboratory confirmed COVID-19 in adults and children hospitalized with severe disease. Severe disease is defined as patients with an oxygen saturation (SpO2) ≤ 94% on room air, or requiring supplemental oxygen or requiring mechanical ventilation or requiring extracorporeal membrane oxygenation (ECMO).	Infectious disease caused by SARS-CoV-2 (adults and children as per dosing)	Remdesivir when used as part of a compassionate use program, is indicated for the treatment of adults ≥12 years old with COVID-19 who require invasive mechanical ventilation. Updated indication (May 2020): For the treatment of adult and pediatric patients from 12 year of age weighing at least 40 kg with severe COVID-19 (hospitalization requiring supplemental oxygen, noninvasive ventilation, high-flow oxygen devices, invasive mechanical ventilation, or ECMO), confirmed by PCR, or who have known contact with a confirmed case of COVID-19, with PCR pending.	Remdesivir is indicated for the treatment of coronavirus disease 2019 (COVID-19) in adults and adolescents (aged 12 years and older with body weight at least 40 kg) with pneumonia requiring supplemental oxygen.
Dose	200 mg for 5 days (possible extension to 10 days) Children ≤40 kg 5, then 2.5 mg/kg	200 mg for 5 days (possible extension to 10 days) Children ≤40 kg 5 then 2.5 mg/kg	200 mg for 1 day then 100 mg for 9 days	200 mg on day 1 then 100 mg per day for 5 to 10 days
Other conditions/requirements		* pending Council decision on full conditions To submit results of ongoing clinical trials	Medicinal product subject to restricted medical prescription. Treatment should be initiated in hospital setting only	Requirements for further quality data, and efficacy (ongoing trials) and safety studies (specific obligations) in particular in renal or hepatic impaired patients and in pregnant and lactating women.
Patient consent required?	Health-care providers and patients/surrogates must be provided with fact sheets about remdesivir that make it clear that it is an investigational product.	To obtain informed consent from patients because this drug is approved as Special Approval	Consent no required	Not required
Pharmacovigilance measures	Reporting of ADRs to Gilead and Gilead reports to FDA as well	To submit ICSRs to MHLW/PMDA To develop and implement RMP	CHMP imposed a number of conditions including safety reporting on prescribers and on Gilead	Risk management plan increased pharmacovigilance measures
Territory	U.S.A.	Japan	Request made by Estonia, Greece Romania, The Netherlands CHMP CU Opinion used by Austria, Romania, Slovenia. CU at national level in practically all other MSs	EU + Norway, Iceland, Liechtenstein
Distribution	Managed by U.S. government	Gilead to report names of clinical institutes and its amount which MAH deliver the product	Distribution by Gilead (limited availability)	Access managed by Gilead
Liability immunity	yes	No	No	No

2.1. United States

The U.S. FDA has an Emergency Use Authorization, which it can use following a declaration of a public health emergency by the Secretary of the Department of Health and Human Services [7].

Under this authority, the FDA may authorize unapproved medical products or unapproved uses of already approved products to treat, prevent, or diagnose serious or life-threatening conditions when there is not an adequate, approved, and available alternative. An EUA is different from a marketing approval and is based on a different standard of evidence. For an EUA to be approved, FDA makes a determination, based on available evidence, that the product may be effective for the intended use and that its known and potential benefits outweigh its known and potential risks. What constitutes acceptable evidence varies with the disease and context of the EUA itself. As part of every EUA specific parameters for how the product may be used are stated, distributed, patient eligibility and dosing, and administration. Informed consent by patients is not specifically required, but Fact Sheets for Healthcare Providers and patients are part of the EUA approval and required to be employed at the point of care. An EUA has no specific sunset but ends when the circumstances justifying the EUA no longer exist, or when a change in the approval status of the product means the EUA is no longer needed.

On 1 May 2020, the FDA issued an Emergency Use Authorization for remdesivir [8]. The letter of authorization provided for the indication and conditions of the EUA and the company donated the product to the U.S. government for distribution to hospitals by state health departments. Clinicians utilizing remdesivir must adhere to the terms of use and are required to report medication errors and serious adverse events considered to be possibly associated with the drug to FDA through the MedWatch reporting system or through the company [9]. Efficacy information does not need to be reported. Hospitals must maintain records of how the product is allocated and dispensed. It is noteworthy that in keeping with remdesivir being an investigational product, firm restrictions are placed on any printed material provided related to the EUA provided to patients or clinicians, including that it may not be stated or suggested that the product has been shown to be safe and effective and its use is only under the terms of the EUA. Liability immunity for the countermeasures is borne by HHS.

Other avenues of access to remdesivir that were in place before the EUA continues, including through clinical trials and individual patient Investigational Drug Applications (commonly known as emergency INDs) for circumstances not covered by the EUA, such as less severe disease, highly complex circumstances, or use in pregnant women. The company maintains responsibility for a number of aspects of the EUA program, including providing all adverse event data it received to FDA.

2.2. Japan

Japan through its Ministry of Health, Labour and Welfare (MHLW) and its Pharmaceuticals and Medical Devices Agency (PMDA) has a Special Approval for Emergency (SAE), defined in article 14–3 of the Pharmaceuticals and Medical Devices Act. A certain medical product may be approved under this provision when 1) an emergency situation requires an unapproved medical product to be used to prevent damage to public health caused by the spread of diseases, 2) such emergency situation cannot be managed appropriately by any means other than the use of the unapproved product, and 3) such a product is legally available in a country with a regulatory system for medical products that is equivalent to Japan. A designation by Cabinet Order is necessary to allow the SAE. After the designation, the application for a product meeting the above criteria can be submitted. PMDA will prepare a report within a very short timeframe, and the report will then be discussed by the Pharmaceutical Affairs and Food Sanitation Council (MHLW). If the Council recommends approval, the Minister of Health, Labour and Welfare then grants the Special Approval for Emergency. The review timeline for the SAE is much shorter than a regular authorization. The Minister can require the approval holder to implement routine and additional pharmacovigilance, such as all-case use result survey. The Minister can withdraw the approval where the emergency conditions no longer persist, or the withdrawal is necessary to prevent damage to public health.

On 7 May 2020, the Japanese Authorities made use of the legal framework and issued a SAE of remdesivir, referring to the EUA granted in the U.S. on 1 May [10]. The Ministry of Health, Labour and Welfare considered that remdesivir satisfied the conditions after designation by the Cabinet Order on 2 May. The New Drug Application was submitted to PMDA on 4 May, including the available clinical trial data. PMDA prepared the report including the approval conditions and labeling. The report was discussed by Pharmaceutical Affairs and Food Sanitation Council (MHLW) on 7 May, which recommended approval as SAE to the Minister. Remdesivir was approved on the same day for the treatment of patients with COVID-19, and approval conditions for Japan include in particular a risk management plan, the written informed consent, and all-use case surveillance.

2.3. European Union

In contrast, the European Union has no formal emergency use authorization as such, but it has several tools it can use in the event of an emerging threat or outbreak.

A Compassionate Use opinion can be issued at the EU level for medicines intended for patients with a chronically or seriously debilitating disease or whose disease is considered to be life-threatening, and who cannot be treated satisfactorily by an authorized medicinal product. A compassionate use opinion may be requested by any EU Member State to the European Medicines Agency Committee for Medicinal Products for Human Use (EMA CHMP) for medicines undergoing clinical trials or under review. Each Member State is then free to make use of this opinion at the national level and only needs to inform EMA when it does so. The request for a centralized opinion does not come from the company, but the company must submit available data, and is obliged to adhere to a set of general conditions related to manufacturing, distribution, and safety monitoring. An opinion by the CHMP does not prevent the Member States from recommending the medicine as part of their national systems of compassionate use, yet the Regulation does mention ‘ … a common approach should also be followed, whenever possible, regarding the criteria and conditions for the compassionate use of new medicinal products under Member States’ legislation,’ with the aim to meet the legitimate expectations of patients in the Union. Compassionate use programs complement the possibility of enrolling patients in clinical trials.

The EU approach is also supported by a Public Health Threats Plan, designed to enable a quick EU response to global emergencies such as pandemics [11]. The plan provides for regulatory agility, including rapid scientific advice and fast-track approval of medicines in such circumstances. An emergency task force is set up to prioritize and fast-track applications as necessary.

Companies can also submit applications to EMA for Conditional Marketing Authorization (CMA) of medicines for chronically, seriously debilitating, or life-threatening diseases, and the CMA can obviously be used for medicines used in a pandemic. A CMA is agreed by the EMA CHMP upon review of usually clinical limited datasets, but in the case of a public health threat, incomplete non-clinical and quality datasets may also be accepted. The critical condition is that a positive benefit/risk balance needs to be established and the CHMP must be convinced that the benefits of immediate availability on the market outweigh the risks of unknowns due to limited datasets, while data continue to be collected [12].

Specific obligations are imposed on the company to ensure that complementary data, including from new or ongoing efficacy or safety trials, are submitted within a defined timeframe. More stringent pharmacovigilance is imposed. As more data become available, the CHMP will review and confirm whether the positive benefit/risk balance is maintained, or changes are required; otherwise, the authorization can be suspended or revoked.

On 3 April 2020, the EMA issued a CHMP scientific opinion on compassionate use of remdesivir [13]. This opinion was based mostly on efficacy in animal models of SARS-Cov2 and MERS-Cov as no clinical efficacy data were available and remdesivir’s safety profile was incompletely characterized [13].

On 30 April, EMA-CHMP initiated a rolling review of remdesivir with a view to recommend, or not, a Marketing Authorization for remdesivir. Considering the scarcity of available but positive data at that time, and high probability for obtaining further data, the appropriate legal framework was a Conditional Marketing Authorization (CMA). While the CHMP rolling review was ongoing, on 11 May the compassionate use opinion was revised to widen the scope of indication and include patients who have a SpO2 ≤ 94% or require supplemental oxygen, in line with the data from the NIAID trial.

A submission for CMA was made to EMA on 5 June 2020, and the CHMP issued a positive risk-benefit opinion on 25 June 2020 [14]. This opinion was followed by a Marketing Authorization decision issued by the European Commission on 3 July 2020. Safety monitoring is defined in the Risk Management Plan published at the same time [14].

As of 25 June, there was no formal regulatory approval for remdesivir in Canada or Switzerland, but the drug was available in compassionate use.

3. Discussion

Within days of the NIAID trial’s interim results being released, remdesivir would become a standard of care for treatment, for example, in the U.S., Japan, and Europe for seriously ill COVID-19 patients, even though it remains an investigational product and trials are still underway. The mechanisms of emergency access, by design, acknowledge the risks and uncertainties inherent in authorizing widespread access to investigational treatments, but also their potential importance in the face of life-threatening illness with no alternative treatments. Given the speed with which data are being collected and analyzed, regulators are not able to have access to the depth and details that are customary for marketing application reviews. Each regulatory authority has slightly different ways of implementing these provisions, but their intent is the same. By sharing information on a continual basis, they have also facilitated the swift regulatory approval for emergency use.

While the EUA in the U.S. and compassionate use approvals in some other countries (e.g. France) for hydroxychloroquine were granted on very limited, non-comparative data, the EUA for remdesivir was granted on much more robust data emerging from a well-conducted trial with a large number of patient participants. The FDA EUA for hydroxychloroquine was granted on 28 March 2020 and revoked on 15 June 2020 [15]. Early access programs are not without risk. For example, with in-depth review of the full dataset, remdesivir may be found to not have the safety and efficacy including survival benefit suggested. This is part and parcel of the reality of early clinical data and a risk that the regulatory provisions themselves take into full account. It is why every regulatory paradigm for emergency access requires, in some form, for prescribers and patients to be informed of the investigational status of the treatment.

There is also a serious risk that emergency use provisions interfere with enrollment in clinical trials. It is essential that randomized controlled trials continue, confirm, and complete the preliminary data that are available to date [16]. This message has been made public by each of the three authorities and is part of the statement from the International Coalition of Regulatory Authorities on COVID-19 [1]. It was explicit in the Compassionate Use opinion in Europe, and although the EUA procedures do not specifically require this to be addressed, FDA takes it into account in the terms of the EUA itself. Regulators are also aware that prescribers may be reluctant to enroll patients in trials once preliminary data are available. The strength of such preliminary data is critical as we have seen in recent weeks, and there is the risk of drawing early conclusions, which may be incorrect once more data become available.

Regulators are well aware that emergency like regular approvals are only one step toward access for patients. Regulatory agility applied by MHLW/PMDA, EMA, and FDA together with increased data sharing has allowed quick turnaround of procedures that normally take months. However, production and supply will limit access for patients in all countries.

Of note, Gilead, the marketing authorization applicant has announced it entered into an agreement with manufacturers in India and granted licenses to manufacture for countries in South and Central America, Africa, and many Asian countries. This initial approach should be acknowledged as an innovative way of facilitating access to patients all over the world in such exceptional circumstances. The supply is going to be limited, especially in low- and middle-income countries. In any case, as remdesivir use is via the parenteral route, its use will remain limited to more severe forms of the disease, and other treatments and vaccines are urgently needed for the prevention of the disease.

4. Conclusions

Regulators across the world made decisions based on very limited data to make use of their emergency procedures for access to critical medicines for COVID-19. Established intense collaboration and exchange of information on a continual basis has allowed swift approvals to allow exceptional access. Contrary to the U.S. and Japan, the European Union has no formal Emergency Use Authorization and this may be a point of reflection for future legislation. At the same time, regulators agree that when evidence is still lacking, efforts should be made to direct patients toward inclusion in clinical trials and this has been clearly voiced by regulators across the globe.

5. Expert opinion

This article combines the views of three major regulators and highlights the collaboration that took place to make available an antiviral to patients across the globe and brings to the fore several original discussion points.

Emergency approvals for the first antiviral to show efficacy were issued in record time considering that information on COVID-19 was released end of December 2019 and the pandemic was officially declared by WHO on 11 March 2020. In the meantime, thousands of trials were initiated, either as master protocols or individual trials, and reviewed by regulatory agencies. The first results of the trials that were of sufficient quality for regulatory purpose were shared and analyzed in full cooperation between regulators, thanks to confidentiality arrangements allowing regulatory authorities (here EMA, FDA, and MHLW/PMDA) to discuss and exchange preliminary applications and assessments. Of note, remdesivir benefited from its initial development in Ebola, which was unsuccessful but meant that the file was relatively advanced. This said, there are still data that must be generated.

The second element is the impact of approvals by stringent regulatory authorities, as those may serve as reference approvals for many authorities who apply the principle of reliance, i.e. rely on the assessments by other authorities but retain their sovereignty in the decision to approve or not. The International Coalition of Medicines Regulatory Authorities supports this collaboration and organized technical meetings on COVID-19 drugs, trials, vaccines, and observational studies to share information therefore multiplying the impact of these emergency approvals.

The third element is increased regulatory speed. In emergency situations such as the COVID-19 pandemic, it is remarkable that regulatory authorities, regularly criticized for their lack of reactivity, have applied shortened timelines to reduce unnecessary delays while obviously retaining the quality of the scientific assessments as their main objective.

The fourth element is unknown effects in ‘other’ populations and what regulators can analyze and conclude at present. In the case of COVID-19, children may not be the priority population as data show that they are seldom seriously affected by the viral infection; however, there are still some young patients who may benefit from the antiviral. The other population is pregnant women who are affected by serious forms of the disease. It is too early to fully describe the impact of the virus on pregnancies, but high fever and respiratory distress syndromes are clearly major deleterious events for pregnant women. The disease effects on patients from different genetic and social backgrounds show more severity in some groups (black, latinx, and deprived groups). The effect of the antiviral on those groups is unknown at present.

The fifth element is increased transparency. All regulators have increased their level of transparency to explain the measures they take and what the data allow them to conclude. For example, following on its initiatives to disclose the rationale and basis for regulatory opinions, the European Union (European Commission and European Medicines Agency) is making immediately available the assessment reports and is increasing the level of transparency on discussions taking place with developers of medicines.

It is expected that some of these measures and new approaches may become part of routine activities in the interest of patients and early access.

Article highlights

• Emergency regulatory approvals have been granted to the first treatment of COVID-19, remdesivir, based on robust data.

• Three of the major regulatory authorities have made use of such pathways to make the medicine available to patients faster.

• The three authorities exchanged information and collaborated to facilitate approvals.

• Only topline results were available at the time of emergency approvals, which showed shortened time to recovery but only non-statistically significant trend on decreased mortality.

• Early approvals in similar circumstances should not impair patient enrolment in further trials to gather more evidence.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer declarations

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

The assessors in our regulatory authorities who are working hard to deliver safe and effective medical products to patients.