FOI release

Freedom of Information request on the RECOVERY Trial Regulatory Submission by the Chief Investigators on 13 March 2020 (FOI 21/865)

Published 20 January 2022

31st August 2021

FOI 21/865

Dear

Thank you for your email enquiry dated the 30th July 2021.

Regarding your request for the following information:

1. I request access to the RECOVERY Trial Regulatory Submission made by the Chief Investigators on 13 March 2020.

2. Please include any pharmacokinetic modelling provided with the submission for the hydroxychloroquine arm and any data provided to MHRA, from whatever source, that was prepared by the WHO.
3. Please also provide details of any correspondence (by letter or email) between MHRA and the Chief Investigators of the RECOVERY trial or any other interested party on any aspect of the design, specification, or delivery of the RECOVERY trial.

In response to point 1;

The information you have requested is exempt under Section 21 of the Freedom of Information Act (FOIA), because the information is accessible to you, as it is already in the public domain.

The information requested is publicly available on the Recovery website and the link provided below for your reference; https://www.recoverytrial.net/for-site-staff/site-set-up-1/regulatory-documents

In response to point 2;

The following was provided in protocol version 2.0, 23rd March 2020. This protocol is also publicly available on the RECOVERY website (under substantial amendment 1); https://www.recoverytrial.net/for-site-staff/site-set-up-1/regulatory-documents

Hydroxycholoroquine: Chloroquine (CQ), an antimalarial drug discovered in 1934 and introduced generally in 1947, is the drug to which humans have been most exposed, with an annual global consumption of hundreds of metric tonnes for over 50 years. It is inexpensive, simple to administer, and, at the appropriate doses, has an excellent safety profile in all age groups and has been the prophylactic drug of choice in pregnancy 26. In addition to its antimalarial use both chloroquine and the closely related hydroxychloroquine (HCQ) are used in continuous daily dosing for rheumatoid arthritis, systemic and discoid lupus erythematosus and psoriatic arthritis. HCQ is reported to have better safety profile than CQ, better gastrointestinal tolerability, and less retinal toxicity27. 27.McChesney EW. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate. Am J Med 1983;75:11-8

CQ has significant antiviral activity against SARS-CoV-2 in cell culture (EC50 = 1.13 μM; CC50 > 100 μM, SI > 88.50), as it does for the related SARS-CoV-1 28-31. CQ blocks virus infection by increasing endosomal pH required for virus/ cell fusion, as well as interfering with the glycosylation of cellular receptors of SARS-CoV.30 In SARS-CoV-2 infected Vero cells, HCQ (EC50=0.72 μM) has been reported to be more potent than CQ (EC50=5.47 μM) 32, although Liu et al reported that CQ was more potent than HCQ.33 These are relatively high levels by comparison with therapeutic exposures in the treatment of malaria but could be achieved with daily oral dosing. Chloroquine has complex pharmacokinetic properties and although the relationship between plasma concentrations and concentrations in respiratory epithelium is not known precisely, in rats the concentration in lung is between 124 and 748-fold that in plasma 34. If active, HCQ concentrations in the human lung would be expected to exceed those required for the EC90 after an initial dose. There are preliminary reports emerging from China and France of clinical benefit in the treatment of COVID-19 infections

The recommended adult dosing of chloroquine for treatment of non-falciparum malaria (BNF) is: Initially 620 mg, then 310 mg after 6–8 hours, then 310 mg daily for 2 days. This is equivalent to 930mg base in first 24 hours. This is a loading dose to ensure the necessary blood concentrations are achieved rapidly.

Hydroxychloroquine is very similar to chloroquine. It is used mainly to treat rheumatoid arthritis and other related conditions. The adult dose is usually 400-600mg/ day (equivalent to 310 to 465 mg base). Sometimes 800mg/day is given. The dose in RECOVERY is Hydroyxchloroquine (155mg base per 200 mg tablet):

Initial dose: 4 tablets

6 hours later: 4 tablets

12 hours: 2 tablets

24 hours: 2 tablets

Thereafter: 2 tablets every 12 hours for a total of 10 days

12x155mg = 1860mg base = in first 24 hours

So the loading dose in RECOVERY is twice the normal dose for treating malaria. However, this dose has been selected based on the available data of the IC50 for SARS-CoV-2. The objective is to reach plasma concentrations that are inhibitory to the virus as soon as safely possible. The plasma concentrations that will result are at the higher end of those encountered during steady state treatment of rheumatoid arthritis. Given the significant mortality in patients hospitalised with COVID-19, this dose is felt to be justified. This is the schedule that is likely to be adopted by the World Health Organisation. No dose adjustment is required for weight based on the doses defined in this protocol.

In response to point 3;

The information you have requested is exempt under Section 12 of the Freedom of Information Act (FOIA), because to provide the information would require an unreasonable use of resources.

Section 12 of the FOI Act allows public authorities to refuse requests where the cost of dealing with them would exceed the appropriate limit, which for central government is set at 24 working hours in determining whether the department holds the information, locating, retrieving and extracting the information. As your current request concerns a large volume of emails and documents, unfortunately, it would take us more than 24 working hours to locate, retrieve and extract the information.

We advise that you narrow your request, for example, by restricting your FOI request to correspondence from a specific time period or issue, or one particular document you are interested in obtaining.

Please note that substantially similar requests made within 60 working days of an original request can be aggregated into one for the purposes of calculating a cost limit, meaning that Section 12 could still apply.

If you disagree with how we have interpreted the Freedom of Information Act 2000 with regards to your request, you can ask for the decision to be reviewed. The review would be carried out by a senior member of the Agency who was not involved with the original decision.

If you have a query about the information provided, please reply to this email.

We now consider this request closed.

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Yours sincerely,

MHRA Customer Services