Joshua Beddow, Junior Analyst at Lightning Health takes a look at the early market access for remdesivir in Europe.

Introduction

Remdesivir is an antiviral medication, that was originally developed for the treatment of the Ebola virus.¹ Researchers began a clinical trial in February 2020 to test the efficacy of remdesivir for the treatment of COVID-19,² and by April 2020, early results indicated that remdesivir accelerates recovery for hospitalised patients with severe COVID-19.³ On 1^st May 2020, remdesivir became the first drug to receive emergency use authorisation from the U.S. Food and Drug Administration (FDA), for the treatment of people hospitalised with COVID-19.⁴ By 25^th June 2020, the human medicines committee at the European Medicines Agency (EMA) recommended conditional authorisation for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen.⁵ Given the urgent need for patient access, a range of early access mechanisms were implemented across Europe in 2020, prior to formal health technology assessment (HTA) and pricing and reimbursement decisions.

UK

Early Access to Medicines Scheme (EAMS):

In advance of marketing authorisation, remdesivir was approved by the Medicines and Healthcare products Regulatory Agency (MHRA) for use in the UK through the EAMS from 26^th May until 3^rd July 2020. The MHRA decision for early access was based on the results from clinical studies demonstrating that remdesivir reduced the mortality rate and the time for recovery from 15 days to 11 days for patients with severe COVID-19. During this time, the medicine was made available free of charge to the NHS for the treatment of hospitalised patients with COVID-19.⁶

NHS commissioning policy:

Following the expiry of the EAMS agreement and the granting of marketing authorisation in June 2020, the NHS published an interim commissioning policy for remdesivir. This policy recommended that remdesivir be made available as a treatment option through routine NHS commissioning for hospitalised patients (adults and children 12 years and older) with COVID-19, in accordance with the licensed indication. NHS England and NHS Improvement set out the first version of the interim commissioning policy in July 2020, with the second version issued in November 2020. This latest document states that remdesivir should not be initiated in patients presenting to hospital >10 days after symptom onset, and should not be initiated in patients who are unlikely to survive (based on clinical opinion).⁷

National Institute for Health and Care Excellence (NICE) Appraisal:

One month following publication of the NHS interim commissioning policy, the draft scope for a NICE appraisal was published in August 2020, with the objective of determining the clinical and cost-effectiveness of remdesivir for the indicated patient population. The main outcomes for consideration were time to recovery, length of illness, time to return to normal activities, virological outcomes (viral shedding and viral load), mortality, adverse effects of treatment, and health related quality of life (QoL). The relevant comparator was identified as established clinical management with or without dexamethasone.⁸ On 8^th April 2021, remdesivir received a conditional NICE recommendation to be considered for five days for the treatment of COVID-19 pneumonia in adults and young people 12 years and over, weighing 40kg or more, who are in hospital and on supplemental oxygen but not on invasive mechanical ventilation. NICE was aware of the difference between their recommendations for remdesivir and those issued by the World Health Organization (WHO) but believed that the benefits outweigh the potential risks for most patients. Alongside this, NICE has also instructed that remdesivir should not be used in patients who are on invasive mechanical ventilation, except within the context of a clinical trial setting.⁹

France

Authorisation for Temporary Use:

Two weeks after obtaining a conditional European marketing authorisation, in July 2020, the Agence nationale de sécurité du médicament et des produits de santé (ANSM) granted remdesivir a cohort authorisation for temporary use (ATUc). This ATUc allowed reimbursed access to remdesivir for the treatment of COVID-19 in adults and adolescents (aged 12 years and over and weighing at least 40kg) with pneumonia requiring oxygen therapy, in advance of the formal Transparency Committee assessment. The ATUc required any initiation of treatment to be the subject of a collegial opinion, and the collection of data for patients receiving treatment under this programme.^10,11,12 Following the results of four different clinical trials containing 7,333 hospitalised patients, it was determined by the WHO that there was a lack of evidence for remdesivir in terms of reducing mortality, the need for mechanical ventilation and reduced time to clinical improvement. The provision of the medicine under the ATUc was stopped on 24^th October 2020.¹³

Transparency Committee Assessment:

The Transparency Committee assessment of remdesivir was published in October 2020, based on the results of three comparative studies carried out in hospitalised patients. The medical service rendered (SMR) for remdesivir was Insufficient (no reimbursement) for patients requiring oxygen therapy at high flow rate, or oxygen therapy during non-invasive or invasive assisted ventilation or extracorporeal membrane oxygen (ECMO) therapy. The SMR was considered low for patients hospitalised for COVID-19 with pneumonia requiring low flow oxygen therapy. Furthermore, the improvement of actual benefit (ASMR) was rated as ‘absent’ (ASMR V) due to the lack of effect on reducing mortality, lack of data on the efficacy according to the stage of disease, and lack of data on the impact on the expected negative viral load. Prior to the announcement of the Transparency Committee assessment, the manufacturer withdrew the reimbursement request for remdesivir in September 2020.¹⁴

Germany

Remdesivir is available in Germany as a result of the conditional marketing authorisation issued by the EMA in June 2020 (compassionate use was not available before regulatory approval). In line with the standard process in Germany, reimbursement was available directly following EMA approval, with a subsequent assessment of the added therapeutic benefit over the current standard of care (SoC) required from the Gemeinsamer Bundesausschuss (G-BA). In October 2020, the German government requested around 5% of the supply of remdesivir under a six-month European Union supply deal with the manufacturer, despite criticism of the deal within the German media due to the outcomes of the WHO study¹⁵. On 1^st April 2021, the G-BA began the benefit assessment for remdesivir in patients with COVID-19, 12 years and older, who require additional oxygen supply. The publication of this assessment will take place on 1^st July 2021 and the eventual resolution is expected around mid-September 2021.¹⁶

Italy

Compassionate use:

Remdesivir was authorised in Italy in March 2020 for use in two specific randomised phase III studies, and then for a phase II/III single arm open label study (in children/adolescents) in August 2020. This authorisation occurred under Agenzia Italiana del Farmaco’s (AIFA) emergency authority to evaluate all clinical trials on medicines for patients with COVID-19 (Decree Law “Cura Italia” Art. 17).¹⁸ Approval from AIFA for compassionate use in all clinical trials with COVID-19 patients was then granted later in March 2020, the cost of which was covered by the manufacturer. This also took place around the time of compassionate use authorisations for similar programmes, such as: ribavirin for inhalation solution (Bausch Health) (approved 24^th April 2020); solnatide (APEPTICO Forschung und Entwicklung GmbH) (approved 15^th April 2020); canakinumab (Novartis) (approved 7^th April 2020); and ruxolitinib (Novartis) (approved 2^nd April 2020).¹⁷

AIFA assessment:

In September 2020, AIFA released guidance for prescribing remdesivir for the treatment of patients with COVID-19,²⁰ which was updated in November 2020 to reflect additional evidence that had become available.¹⁹ AIFA established that due to new evidence from the WHO SOLIDARITY trial, even with the population eligible for reimbursement (patients with COVID-19 pneumonia on oxygen therapy not requiring high-flow oxygen or mechanical ventilation or ECMO, and with symptom onset of less than 10 days), use can only be considered in selected cases, after an accurate evaluation of the benefit/risk ratio.²¹

Spain

Compassionate use:

On 17^th March 2020, remdesivir was approved for use within the environment of a clinical trial in Spain, however later that month Agencia Española del Medicamento y Productos Sanitarios (AEMPS) suspended access to remdesivir for compassionate use, except for pregnant patients and seriously ill minors. As of May 2020, compassionate use of remdesivir was permitted again for hospitalised patients with COVID-19 infections and serious illness.²²

AEMPS assessment:

The Group of Coordination of Therapeutic Positioning (GCPT) agreed to start working on the Informes de posicionamiento terapéutico (IPT) report for remdesivir in August 2020. The IPT was published on 14^th April 2021 and concluded that the available data do not confirm an improvement in mortality, with a high level of uncertainty regarding the clinical relevance of the benefit of treatment. The IPT also noted that the safety profile is not fully characterised and there is a lack of data on the in vivo antiviral activity of remdesivir against COVID-19. Due to this, AEMPS stated it is necessary to evaluate the treatment again with an additional study to address these issues. The IPT concludes that until more information is available, and in the current circumstances of exceptionality and scarcity of effective alternatives, the use of remdesivir might be acceptable in patients who require low-flow oxygen and are still in the initial phase of disease, without currently being able to ensure the relevance of its clinical benefit.^23,24

Conclusion

The example of remdesivir illustrates the broad range of approaches across European healthcare systems for supporting the rapid access for new therapies with potential to address high unmet needs within a global pandemic. This ranges from the use of a customised rapid access pathway in the UK (with the development of an interim NHS commissioning policy for use in advance of a NICE appraisal), to the use of established early access and compassionate use programmes in France, Italy, and Spain, and the use of the standard reimbursed market access pathway in Germany.

This case study illustrates the high level of variation between European markets in terms of the rapid access pathways for new medicines, and how they integrate with the formal HTA and pricing and reimbursement pathways allowing effective emergency powers to grant rapid access, whilst maintaining coherent clinical review of finalised or established data. In future, manufacturers engaging with these processes should retain an awareness that although high levels of unmet need will be a consideration in granting conditional access for a new medicine with an acceptable benefit/risk profile, HTA authorities/payers are unlikely to relax their expectations for a robust demonstration of (incremental) clinical efficacy informed by ongoing data collection to inform their evaluations for pricing and reimbursement but still retain the ability to respond to new evidence when it becomes available.

References

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Article published 13 May 2021.