Authorising medicines in a public health emergency
In the COVID-19 public health emergency, medicines and vaccines were assessed and authorised at speed: the European Medicines Agency set out rapid procedures for each step of the regulatory pathway and gave opinions on medicines before any authorisation existed, the United States authorised unapproved products for emergency use alongside programmes to speed their development, and once the emergency ended the extraordinary measures were phased out and the lessons for future emergencies collected.
Rapid procedures in the EU
On 4 May 2020 the European Medicines Agency (EMA) published an inventory of rapid procedures that can accelerate every step of a medicine's regulatory pathway, so that marketing authorisations of safe, effective and high-quality COVID-19 medicines and vaccines could be granted as soon as possible, and stated that it was fully mobilised to deliver these fast-track assessments in the shortest possible timeframes while ensuring that robust scientific opinions were reached. These rapid procedures stemmed from the agency's emerging health threats plan, and the flexible and fast review was supported by its pandemic task force, which brought together the best scientific experts of the EU regulatory network and would work closely with the agency's human medicines committee (CHMP) to coordinate activities related to the development, authorisation and safety monitoring of COVID-19 medicines and vaccines.
For products under development, in early stages or before a marketing authorisation application is submitted, the mechanisms included:
- rapid scientific advice, giving developers prompt guidance on the best methods and study designs to generate robust data on how well a medicine or vaccine works and how safe it is, and on the manufacturing and control process that establishes its quality, with fees waived and the procedure cut to at most 20 days from the usual 40 to 70
- rapid agreement of paediatric investigation plans, in 20 days rather than up to 120 days of active review, with the compliance check that precedes an application, where one is needed, cut to 4 days
Member states set up compassionate use programmes to give patients access to treatments still in development and not yet authorised, and the agency could recommend how such medicines should be used in them, to support a harmonised EU-wide approach.
Under EU pharmaceutical legislation the standard evaluation of a medicine takes at most 210 active days, but marketing authorisation applications for COVID-19 products were expedited:
- rolling review, a procedure for public health emergencies, let the agency assess data for a promising medicine as they became available, whereas normally all supporting data must be submitted at the start of evaluation; CHMP rapporteurs were appointed while development was ongoing, several review cycles could be carried out for one product as data continued to emerge, each taking about two weeks depending on the amount of data, and once the data package was complete the developer submitted a formal application, processed on a shortened timetable
- accelerated assessment could cut the review of products of major public health interest from 210 days to under 150, and to the absolute minimum where the need was urgent
The rapid procedures were also available for extensions of indication of already approved medicines being repurposed against COVID-19. The agency stood ready to apply further flexibility wherever it was established that shortening another procedural step could have an important public health impact. Rapid approval would be possible only if applications were supported by robust, sound scientific evidence that allowed the agency to conclude on a positive benefit-risk balance. All the accelerated mechanisms required well-prepared dossiers, so the agency encouraged developers to make contact as soon as possible to discuss their evidence-generation strategy; initial discussions depended on the maturity of the development, and the most relevant proposals had priority.
On 20 March 2020 the European Commission, the EMA and the national heads of medicines agencies published recommendations for sponsors on managing clinical trials during the pandemic, which included specific advice on starting new clinical trials of COVID-19 treatments, in particular on the need for large, multinational trial protocols. The advice was in line with the CHMP's call for robust methodology in clinical trials of potential COVID-19 treatments or vaccines.
On 25 June 2020 the CHMP recommended a conditional marketing authorisation for remdesivir, as Veklury, for adults and adolescents from 12 years with pneumonia requiring supplemental oxygen. Remdesivir was the first COVID-19 medicine recommended for authorisation in the EU, and its data were assessed in an exceptionally short time through a rolling review: from 30 April the committee assessed quality and manufacturing data, nonclinical data, preliminary clinical data and safety data from compassionate use programmes, well before the formal application of 5 June. The recommendation rested mainly on one trial, sponsored by the US National Institute of Allergy and Infectious Diseases, which compared a planned ten-day course with placebo in over 1,000 hospitalised patients. Overall, time to recovery was about 11 days with remdesivir against 15 with placebo, and 12 against 18 in severe disease, about 90% of the population; there was no difference in mild to moderate disease or in patients already on mechanical ventilation or ECMO when they started treatment. Data on the proportion of patients who died up to 28 days after starting treatment were being collected for final analysis. On the available data the agency considered the benefit-risk balance shown to be positive in patients with pneumonia requiring supplemental oxygen, that is, the patients with severe disease. To characterise its effectiveness and safety better, the company had to submit the final study reports by December 2020, and further quality data and the final mortality data by August 2020. During the assessment the committee had the support of experts from the pandemic task force, which was established to bring together the most relevant expertise of the European medicines regulatory network to assist member states and the European Commission with the development, authorisation and safety monitoring of COVID-19 medicines and vaccines.
In December 2020 the agency established OPEN, initially as a pilot, as a framework to increase international collaboration and share scientific expertise on the evaluation of COVID-19 vaccines and therapeutics. All COVID-19 vaccines and therapeutics evaluated since the pilot's launch were assessed under it, and participating non-EU experts attended and contributed to the evaluations of the CHMP and the agency's Emergency Task Force.
EU opinions before marketing authorisation
In March 2021 the CHMP completed reviews of monoclonal antibodies for COVID-19 — the casirivimab and imdevimab combination (REGN-COV2), the bamlanivimab and etesevimab combination, and regdanvimab — to provide a harmonised scientific opinion at EU level supporting national decisions on their possible use before marketing authorisation. These monoclonal antibodies had shown activity against SARS-CoV-2. They were designed to attach to the virus's spike protein and so reduce its ability to enter the body's cells, the two antibodies of each combination attach to the spike protein at different sites, and using a combination was expected to have a greater effect than using a single antibody. The agency concluded that both combinations, and regdanvimab in adults, could be used for confirmed COVID-19 in patients who did not need supplemental oxygen and were at high risk of progressing to severe disease, and that bamlanivimab alone, despite uncertainties about the benefits of monotherapy, could be considered a treatment option. Preliminary results showed REGN-COV2 reducing viral load more than placebo and leading to fewer COVID-19-related medical visits. For bamlanivimab and etesevimab the agency had not yet evaluated the full data set, so it was too early to conclude on the benefit-risk balance. The first part of an ongoing study in adult outpatients with mild to moderate symptoms who did not need supplemental oxygen suggested that regdanvimab may lower the rate of hospitalisation, but the results were not robust enough for a firm conclusion on its benefits. Most side effects of REGN-COV2 and of regdanvimab were mild or moderate, and infusion-related reactions, including allergic reactions, had been seen with REGN-COV2 and should be monitored for. The agency started rolling reviews of these antibodies on the preliminary results, evaluating all data, including evidence from clinical trials as it became available, until enough evidence supported formal marketing authorisation applications, assessed against the usual standards for effectiveness, safety and quality; the overall timeline could not yet be forecast, but the process should be quicker than a regular evaluation because of the time gained during the rolling review.
On 22 March 2021, after media reports and publications on ivermectin, the agency reviewed the latest published evidence from laboratory studies, observational studies, clinical trials and meta-analyses and concluded that the available data did not support its use to prevent or treat COVID-19 outside well-designed clinical trials. In the EU ivermectin is approved as tablets for some parasitic worm infestations and as skin preparations for conditions such as rosacea, and it is authorised for veterinary use in a wide range of animal species against internal and external parasites. Laboratory studies found that it could block the virus's replication, but only at concentrations much higher than authorised doses achieve, so toxicity at such doses could not be excluded. Although ivermectin is generally well tolerated at the doses authorised for other indications, side effects could increase with the much higher doses needed to reach effective concentrations in the lungs. Clinical results were varied, some studies showing no benefit and others a potential one, and most were small, with other limitations including different dosing regimens and concomitant medications. Further well-designed, randomised studies were needed to conclude whether it is effective and safe in preventing and treating COVID-19. The statement was endorsed by the agency's pandemic task force, in light of the ongoing discussions on the use of ivermectin against COVID-19.
Emergency use authorisation in the United States
By late January 2020 the FDA had announced that it was employing the full range of its public health authorities to facilitate the development and availability of investigational medical products. On 31 January the Department of Health and Human Services declared COVID-19 a US public health emergency and an emergency use authorisation (EUA) needed to mitigate its threat, which enabled the FDA, in consultation with the NIH and the CDC, to authorise the emergency use of unapproved medical products. In early February the first EUA for an RT-PCR COVID-19 diagnostic was issued, for use in CDC laboratories, and EUAs followed for equipment to protect health care workers and treat patients and for further diagnostics at non-CDC laboratories, including home testing kits; FDA guidance on diagnostic testing in May 2020 enabled further options such as rapid antigen tests. WHO formally declared a pandemic on 11 March 2020.
The first EUA for a COVID-19 therapeutic, in March 2020, went to the antimalarials hydroxychloroquine and chloroquine. In May 2020 the FDA issued guidance to expedite the development of COVID-19 products, on initiating pre-IND discussions and on study design, including patient selection, endpoints and analyses; guidance on vaccine development followed in June and was updated in October and in February 2021 to set out the vaccine EUA process. EUAs then went to 9 further products, among them an antiviral in May, convalescent plasma in August, monoclonal antibody regimens in November and the first vaccines in December 2020. The EUA for the antiviral remdesivir led to its approval in October 2020 as the first COVID-19 treatment under the Coronavirus Treatment Acceleration Program. Issued EUAs continued to be monitored, and in some cases this led to withdrawal, as for hydroxychloroquine and chloroquine when conflicting data, including a randomised controlled trial, called the regimen's benefit-risk profile into question.
These therapeutic and biological products were authorised under EUA:
| Date of first EUA (reissued) | Product | Therapy type | Authorised use |
|---|---|---|---|
| 29 March 2021 | Janssen COVID-19 vaccine | Recombinant, replication-incompetent human Ad26-vectored vaccine encoding a stabilised variant of the SARS-CoV-2 S protein | Prevention of COVID-19 in individuals aged 18 or over |
| 18 December 2020 (25 February 2021) | Moderna COVID-19 vaccine | mRNA vaccine | Prevention of COVID-19 in individuals aged 18 or over |
| 11 December 2020 (25 February 2021) | Pfizer-BioNTech COVID-19 vaccine | mRNA vaccine | Prevention of COVID-19 in individuals aged 16 or over |
| 9 February 2021 (25 February 2021) | Bamlanivimab and etesevimab | Antibodies | Treatment of mild-to-moderate COVID-19, with positive direct viral testing, in adult and paediatric patients aged 12 or over, weighing at least 40 kg and at high risk of progressing to severe COVID-19 or hospitalisation |
| 21 November 2020 (25 February 2021) | Casirivimab and imdevimab | Antibodies | Treatment of mild-to-moderate COVID-19, with positive direct viral testing, in adult and paediatric patients aged 12 or over, weighing at least 40 kg and at high risk of progressing to severe COVID-19 or hospitalisation |
| 19 November 2020 | Baricitinib in combination with remdesivir | Antibody + antiviral | Treatment of suspected or laboratory-confirmed COVID-19 in hospitalised adults and paediatric patients aged 2 or over requiring supplemental oxygen, invasive mechanical ventilation or ECMO |
| 23 August 2020 (9 March 2021) | COVID-19 convalescent plasma | Convalescent plasma | Treatment of hospitalised patients with COVID-19 |
| 13 August 2020 | Sodium chloride and sodium citrate renal replacement and regional solution for anticoagulation of the extracorporeal circuit | Replacement solution for CRRT | Replacement solution only in adult patients treated with CRRT for whom regional citrate anticoagulation is appropriate, in a critical care setting |
| 8 May 2020 | Propofol 2% | Sedative | Maintaining sedation by continuous infusion in patients over 16 with suspected or confirmed COVID-19 who require mechanical ventilation in an ICU |
| 1 May 2020 (22 October 2020) | Remdesivir for certain hospitalised patients with COVID-19 | Antiviral | Treatment of suspected or laboratory-confirmed COVID-19 in hospitalised paediatric patients weighing 3.5 kg to under 40 kg, or under 12 and weighing at least 3.5 kg |
| 30 April 2020 | Potassium-free and 2, 3 and 4 mmol/L potassium solutions for CRRT haemodialysis and haemofiltration | Replacement solution for CRRT | Providing CRRT to treat patients in an acute care environment during the COVID-19 pandemic |
Remdesivir's EUA of 1 May 2020 first covered adult and paediatric patients hospitalised with severe disease; it was widened to patients irrespective of severity on 28 August 2020, and after remdesivir's approval on 22 October 2020 for hospitalised patients aged 12 or over and weighing at least 40 kg, it was reissued to keep access for hospitalised children weighing 3.5 kg to under 40 kg, or under 12 and weighing at least 3.5 kg.
As of January 2021 a search of ClinicalTrials.gov returned over 3,500 ongoing or starting COVID-19 trials. Trials of preventive and therapeutic products for COVID-19 were set to continue, including in nonhospitalised settings and in different age groups and populations.
Global and US programmes ran alongside the authorisations:
- the ACT Accelerator, a global collaboration to accelerate the development, production and equitable access to COVID-19 tests, treatments and vaccines, with COVAX as its vaccine pillar
- the R&D Blueprint, a global strategy and preparedness plan to fast-track the availability of effective tests, vaccines and medicines that can be used to save lives and avert large-scale crises, whose Global Research Roadmap was released in March 2020
- the Solidarity II collaboration, led by WHO, promoting the implementation of serological surveys of SARS-CoV-2
- the Unity Studies' early investigation protocols, promoting standardised epidemiological, molecular and serological methods to allow international comparisons, so that countries and the global community can address knowledge gaps and inform an evidence-based response
- Operation Warp Speed, a partnership among components of the Department of Health and Human Services, including the CDC, NIH, BARDA and the Department of Defense, with private firms and other federal agencies, which coordinated existing department-wide efforts, including the NIH's ACTIV partnership, the NIH's RADx initiative and work by BARDA, and included vaccine candidates from three companies
- ACTIV, a public-private partnership to speed COVID-19 vaccine and treatment options
- the COVID-19 Prevention Trials Network, which merged four existing NIAID-funded clinical trials networks: the HIV Vaccine Trials Network, the HIV Prevention Trials Network, the Infectious Diseases Clinical Research Consortium and the AIDS Clinical Trials Group
- the Coronavirus Treatment Acceleration Program, a special emergency programme for possible COVID-19 therapies, providing FDA subject-matter expertise for ACTIV initiatives, including on trial design and conduct and on regulatory standards
The Solidarity I adaptive treatment trial reported on 15 October 2020 that remdesivir, hydroxychloroquine, lopinavir/ritonavir and interferon had little or no effect against standard of care on overall mortality, initiation of ventilation or length of stay in hospitalised patients. WHO gave its first emergency use validation to a vaccine on 31 December 2020.
The regulators' decisions compared
In the first half of 2021 the regional regulators' COVID-19 decisions — the FDA's emergency use authorisations, the EMA's conditional marketing authorisations and Health Canada's interim orders — were hard to keep up with, some national agencies expedited access ahead of the regional regulators' decisions, and rolling review had become a commonly employed tool. By late May 2021 the EU had approved remdesivir, conditionally approved two mRNA vaccines and two adenovirus vector vaccines, and endorsed dexamethasone, with four further vaccines under rolling review; the FDA had authorised the Moderna, J&J and Pfizer-BioNTech vaccines for emergency use, as well as several medicines including monoclonal antibodies and remdesivir; and Health Canada had authorised the Moderna and Pfizer-BioNTech vaccines with conditions under an interim order. One regulatory writer holds that the pandemic was beginning to show the value of real-world data combined with data collected through pre-approval pathways.
Adapting vaccines to variants
Viral mutations and their implications for available treatments and vaccines will require monitoring. One regulatory writer holds that, with the ability to use CRISPR technology to modify and re-code RNA vaccines in response to emerging variants, customised vaccines may be developed in a matter of weeks, scaled up and deployed. The same writer holds that this can be considered conceptually similar to minor modifications in drug formulation, as would be represented in an amendment to the new drug application for an already approved drug, and that regulators will need to maintain creativity and impetus to authorise vaccine variants as fast as they are needed.
At a workshop of the International Coalition of Medicines Regulatory Authorities (ICMRA) on 8 May 2023, co-chaired by the EMA and the FDA, regulators noted that authorised vaccines continued to be effective at preventing hospitalisation, severe disease and death, while protection against infection waned over time and as new variants emerged. Preliminary data showed that vaccines adapted to circulating strains improved immunity to recently emerged variants such as XBB descendent lineages. There was broad agreement that vaccine formulations for the coming winter season in the northern hemisphere should include only one virus strain and be based on the XBB family of Omicron subvariants, such as XBB.1.5. The regulators highlighted that such monovalent vaccines could be used for both booster and primary vaccination, the latter, for example, only in young children below 4 to 5 years of age. They noted that authorising or approving a strain change for an already authorised COVID-19 vaccine would require only data on the vaccine's manufacturing and quality and laboratory data, provided that post-authorisation data on vaccine quality, effectiveness, immunogenicity and safety were collected.
The end of the emergency and lessons learned
On 6 July 2023, after the WHO declared the end of the public health emergency in May, the EMA, the European Commission and the Heads of Medicines Agencies began phasing out the extraordinary regulatory flexibilities for medicines put in place during the pandemic to help address its regulatory and supply challenges. The flexibilities covered areas including marketing authorisation and related regulatory procedures, manufacturing and importation of active pharmaceutical ingredients and finished products, quality variations, labelling and packaging requirements, and compliance. During the pandemic the European Commission, the Heads of Medicines Agencies and the EMA also agreed measures to mitigate the impact of the emergency's disruptions on inspections of manufacturing facilities and other sites relevant for medicinal products in the EU. The flexibilities ensured the continued availability of medicines while GMP and GDP standards were adhered to.
From then on the flexibilities introduced jointly during the pandemic should no longer be granted. Labelling flexibilities already approved, such as English-only labels on COVID-19 vaccines, were extended to the end of 2023 to ensure a smooth phase-out and avoid supply difficulties or other disruptions from a sudden change in requirements, after which the regular labelling-exemption mechanisms in the legislation should be followed. On-site GMP and GDP inspections had restarted after being postponed or carried out remotely during the pandemic, though a considerable number of postponed inspections still had to be carried out. The validity of GMP and GDP certificates was extended to the end of 2023, and the GMDP Inspectors Working Group was to issue an update on the approach for 2024. The same group reviewed the remote working arrangements of Qualified Persons during the pandemic and was to issue guidance on how those arrangements can be applied in future. Experience with the flexibilities was being collected by the agency's Executive Steering Group on Shortages and Safety of Medicinal Products, which would consider how the lessons learned could inform best practice for tackling medicine shortages in new and emerging health challenges.
On 25 July 2023 the agency published the report of a workshop its Emergency Task Force and the European Commission held on 9 June 2023 with national competent authorities, representatives of ethics committees and academic sponsors, which collected suggestions for EU-level actions to improve how clinical trials are set up and conducted during public health emergencies. The actions aim to address the barriers met during the COVID-19 pandemic and the mpox outbreak in setting up adequately sized trials across several member states that allow sufficient, high-quality evidence to be gathered rapidly for robust decisions by health authorities. The workshop stressed the need for larger studies across several European countries, faster recruitment and conclusive results on accelerated timelines in an emergency, and its proposed actions fell in two areas:
- processing and approving large multinational trials in an emergency — better coordination between regulators and ethics committees within and across member states, faster assessment and authorisation of applications, exploring flexibilities in implementing the Clinical Trials Regulation, and easier use of the Clinical Trials Information System
- funding and allocating resources, including a coordinating committee to prioritise trials, better ways of identifying and ranking promising compounds, mobilising EU and national funding, and faster contracting of sites
The report recommended that the task force's role of providing scientific advice, reviews and support for large emergency trials should be expanded to include the ethics committees concerned, on a voluntary basis, to discuss and coordinate protocols. The Commission, the EMA and the member states were to take the proposed actions into account in establishing a roadmap for improved clinical trials in public health emergencies. The work on approving trials in emergencies was to be taken forward by the Accelerating Clinical Trials in the EU initiative, a collaboration between the Commission, the Heads of Medicines Agencies and the EMA, and the funding framework discussed with the Commission and member states.