UK access to remdesivir approved: but MHRA criteria exclude some who could benefit

Simon Collins, HIV i-Base

On 26 May 2020 the Medicines and Healthcare products Regulatory Agency (MHRA) issued a press release and guidelines to outline criteria for UK access to remdesivir, the first drug to be approved in the US to treat COVID-19. [1]

However, some people who could benefit are not included. Also, ongoing COVID-19 studies should also now include remdesivir as part of the new standard of care. This is a principle from community engagement in HIV research.

Access to remdesivir will use a programme that allows people with life-threatening illnesses to have early access to medicines that already have proven benefits but that are still going through full approval.

To reach this stage an advisory group (the Commission on Human Medicines) has reviewed the available evidence and recommended that remdesivir is both effective and safe enough for early access. [2, 3]

The UK indication is for:

The treatment of adults and adolescents aged ≥ 12 years and weighing at least 40 kg hospitalised with suspected or laboratory confirmed SARS-CoV-2 infection and severe disease.
Severe disease is defined as an SpO2 ≤ 94% on room air or requiring supplemental oxygen or requiring non-invasive or invasive ventilation or extracorporeal membrane oxygenation (ECMO).

However the document then suggests than remdesivir should be more effective in earlier infection but also this should benefit those at higher risk, and that includes criteria for access. [4]

The criteria are listed below.

Early access criteria

Age 12 years or older on the date of starting treatment.
Weight ≥40kg on the date of starting treatment.
Creatinine clearance above 50 mL/min (upper level defined).
AST/ALT below 5 times upper limit of normal and no history of chronic liver disease defined as Child-Pugh C.

Risk score

Access dependent on having at least four of the following factors (or three if the radiographic severity score threshold is reached).

Radiographic severity score >3.
Male gender.
Non-white ethnicity.
Diabetes.
Hypertension.
Neutrophils >8.0 10 /L.
Age >40 years.
CRP >40 mg/L.

Diagnostic criteria

Less than 10 days from onset of symptoms
Hospitalised with SARS-CoV-2 infection confirmed by PCR collected in preceding 72 hours

Illness severity and organ support criteria

Discussion about the eligibility for escalation to critical care including invasive mechanical ventilation, multi-organ support and CPR should be considered through shared decision making in line with the NICE guidance NG159 (using the Clinical Frailty Score). [5] Some people not eligible for escalation may be suitable for access to remdesivir as determined by mutildisciplinary assessment.
Patient who require FiO2 ≥ 0.4% to maintain O2 sats >94% with standard oxygen therapy (Hudson mask) measured on two occasions at least 1 hour apart; OR who are within 24h of commencing CPAP or HFNO2 to maintain O2 sats >94% and have not been previously mechanically ventilated for treatment of COVID-19
Not requiring invasive mechanical ventilation, ECMO, cardiovascular support (pressor, inotrope or mechanical) at the time of drug initiation. Those starting on the drug should continue if they subsequently need invasive mechanical ventilation. The evidence of benefit has not been demonstrated for those on ventilation. There may be some patients just starting on ventilation in the early phase of the infection who may be suitable for access to remdesivir as determined by mutildisciplinary assessment.

Reporting safety and outcome data is a requirement for use of remdesivir.

Logistic details are outlined for each UK country but trusts will be allocated stock upfront. They will be able to preorder supplies based on caseload and expected need.

comment

The early access to remdesivir is important. It should immediately improve the outcomes for many people who are ill with COVID-19. Even though the protocol requires people to be hospitalised, it should encourage people with confirmed COVID-19 to seek hospital treatment earlier.

Remdesivir has the potential to save lives and earlier access will improve the chance of better outcomes.

So whilst the data clearly show benefit of remdesivir in hospitalised patients, especially for those requiring supplemental oxygen therapy, there remains an issue of supply of remdesivir and therefore the need to prioritise sickest and ‘most at risk’ patients, and exclude patients likely to have poor outcomes.

The current criteria are justifiably stringent in this regard, and will, hopefully become less stringent, as supplies improve over the coming months (and cases hopefully reduce).

There are, however, two criteria that deserve immediate attention.

Patients who are thought unsuitable for ‘escalation’ or Intensive Care are excluded, unless an MDT decides that they are suitable. Actually, this is exactly the group most likely to benefit, if there was a reasonable short to medium term prognosis from a general health point of view, since remdesivir could prevent both progression and the need for ventilatory support.

The second group that should be reconsidered is patients presenting beyond 10 days of symptom onset. These people would also benefit from added anti-inflammatory therapy, however as the ACTT-1 trial showed, time from onset of symptoms was not an important factor for achieving primary outcome.

For patients needing mechanical ventilatory support/ECMO there is clearly a need for added anti-inflammatory therapy.

Finally, all future studies of antiviral and anti-inflammatory or immunomodulatory therapy now need to consider remdesivir as the new ’standard of care’ for comparison.

Rapidly responding to advances in the standard of care was a basic principle of community engagement with HIV research and it is just as important for COVID-19.

STOP PRESS: As this issue of HIV and COVID-19 was being finalised for distribution, Gilead issued a press release on the SIMPLE-Moderate study. Top-line results showed that in moderate COVID-19 disease – those with pneumonia who do not require supplemental oxygen – a 5-day course of remdesivir led to greater clinical improvement than standard of care alone. [6]

References

MHRA. MHRA issues a scientific opinion for the first medicine to treat COVID-19 in the UK. (26 May 2020).
https://www.gov.uk/government/news/mhra-supports-the-use-of-remdesivir-as-the-first-medicine-to-treat-covid-19-in-the-uk
MHRA. Early access to medicines scheme (EAMS) scientific opinion: remdesivir in the treatment of patients hospitalised with suspected or laboratory-confirmed SARS-CoV-2 infection who meet the clinical criteria. (26 May 2020).
https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-scientific-opinion-remdesivir-in-the-treatment-of-patients-hospitalised-with-suspected-or-laboratory-confirme
Product information for healthcare professionals.
https://www.gov.uk/government/publications/early-access-to-medicines-scheme-eams-scientific-opinion-remdesivir-in-the-treatment-of-patients-hospitalised-with-suspected-or-laboratory-confirme (web page)
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/887275/EAMS__11972_0002__TP__HCP_Solution.pdf (PDF direct link)
COVID-19 Therapeutic Alert. Early Access to Medicines Scheme for remdesivir in the treatment of COVID-19. Implementation of the scheme and management of supply. CEM/CMO/2020/025 Issue date: 26 May 2020
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAlert.aspx?AlertID=103046 (web link)
https://www.cas.mhra.gov.uk/ViewandAcknowledgment/ViewAttachment.aspx?Attachment_id=103580 (PDF download)
NICE. COVID-19 rapid guideline: critical care in adults. NICE guideline [NG159]. (Last update 29 April 2020).
https://www.nice.org.uk/guidance/ng159
Gilead press statement. Gilead announces results from phase 3 trial of remdesivir in patients with moderate COVID-19. (1 June 2020).
https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19