Medicines and Healthcare products Regulatory Agency (MHRA)
Dexamethasone – World first coronavirus treatment approved for NHS use by government
On 16th June 2020, the MHRA issued a press release stating that the UK government has immediately authorised the NHS to use the world’s first coronavirus treatment proven to reduce the risk of death.
Dexamethasone, an anti-inflammatory drug, has been immediately approved to treat all UK hospitalised COVID-19 patients requiring oxygen, including those on ventilators, from today.
The drug has been proven to reduce the risk of death significantly in COVID-19 patients on ventilation by as much as 35% and patients on oxygen by 20%, reducing the total 28-day mortality rate by 17%.
The MHRA additionally issued an Alert (Central Alerting System (CAS)) stating that Clinicians should (therefore) consider dexamethasone for the management of hospitalised patients with COVID-19 who require oxygen or ventilation. The Alert was updated on the 24th June 2020 to include information that whereas the coadministration of dexamethasone and remdesivir has not been studied, a clinically significant interaction is unlikely based on metabolism and clearance data. It was noted that dexamethasone was not used in pregnant women.
MHRA regulatory flexibilities resulting from coronavirus (COVID-19)
The MHRA is working closely with the Department of Health and Social Care (DHSC) and other healthcare associates to rapidly identify where flexibilities in the regulation of medicines and medical devices may be possible during the COVID-19 outbreak. Flexibilities described include aspects of Clinical Trials, Marketing Authorisations, Pharmacovigilance, Inspections and Good Practice, Blood Components for Transfusion and Medical Devices. On the 5th June 2020, the MHRA updated their guidance on Medical Devices to include ‘Audits of Notified Bodies and Manufacturers’ by stating that “where feasible, audits of Notified Bodies and manufacturers have been delayed. Remote audits and reviews are being considered as alternatives.”
These regulatory flexibilities are:
- temporary and will be kept under review
- offered to protect people’s health in exceptional circumstances
- effective immediately
Any medicinal product which benefits from these regulatory flexibilities remains subject to marketing authorisation.
MHRA suspends recruitment to COVID-19 hydroxychloroquine trials
Hydroxychloroquine and chloroquine are licensed in the UK to treat different health conditions such as malaria, rheumatoid arthritis, lupus, amoebic hepatitis and abscess and certain dermatological conditions. Recent media reports made suggestions that chloroquine can protect patients from coronavirus or treat COVID-19.
Following the emerging concerns about use of hydroxychloroquine in COVID-19, The MHRA took into consideration the results released from the UK RECOVERY trial, showing no beneficial effect of hydroxychloroquine in patients hospitalised with COVID-19, and a New England Journal of Medicine publication using hydroxychloroquine as postexposure prophylaxis of COVID-19, concluding that hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection. Consequently on 16th June 2020 the MHRA instructed those conducting clinical trials using hydroxychloroquine to treat or prevent COVID-19 to suspend recruitment into their trials.
Action taken to halt sales of fingerprick coronavirus (COVID-19) antibody testing kits
On 29th May 2020, The MHRA asked providers of laboratory-based COVID-19 antibody testing services using capillary blood collected by a fingerprick, to temporarily stop providing this service until home collection of this sample type has been properly assessed and validated for use with these laboratory tests.
Graeme Tunbridge, MHRA Interim Director of Devices, commented that “Use of unvalidated sample types may lead to unreliable results and as such we are working closely with the service providers, laboratories and test manufacturers to resolve the regulatory and patient safety issues. People who have purchased one of these sampling kits, and received an antibody test result, should not consider the result to be reliable and should not take any action based on it.”
This does not affect rapid, point of care tests or laboratory tests performed using blood taken from the vein.
European Medicines Agency (EMA)
On 25th June 2020, the EMA’s human medicines committee (CHMP) recommended granting a conditional marketing authorisation for remdesivir, for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen. The invented name for the medicine is Veklury, and the applicant for this medicinal product is Gilead Sciences Ireland UC.
The CHMP assessed the application under a shorter timeframe and the resulting conditional marketing authorisation will allow Veklury® to be marketed in the EU while still allowing for a thorough evaluation of the medicine’s benefits and risks.
Guidance on remote GCP inspections during the COVID19 pandemic
On the 10th June 2020, the EMA published guidance on Remote Good Clinical Practice (GCP) Inspections to enable their continuity during the COVID-19 pandemic. During the pandemic, on-site inspections may not be possible due to multiple factors such as difficulties and restrictions related to travelling between and within the borders of countries (including travel warnings / restrictions, border controls, transportation difficulties), restrictions to accessing facilities justified by health hazards and local authorities’ recommendations / orders, as well as additional health risks for inspectors and inspectees.
The guidance includes sections on Inspection initiation – impact analysis and feasibility assessment, Inspection preparation, conduct and reporting. References included CPMP/ICH/135/95 Guideline for good clinical practice E6 (R2), Directives 2001/20/EC and 2005/28/EC, and Procedures for preparing/conducting/reporting GCP inspections requested by the EMA (INS-GCP-2, 3, 4).
COVID-19: What’s new
The EMA has been in discussion with the developers of 132 potential COVID-19 treatments (figure correct as of 15th June 2020). Potential COVID-19 treatments currently undergoing clinical trials include:
- Lopinavir/ritonavir (currently authorised as an anti-HIV medicine);
- Chloroquine and hydroxychloroquine (currently authorised at national level as treatments against malaria and certain autoimmune diseases such as rheumatoid arthritis).
- Systemic interferons, in particular interferon beta (currently authorised to treat diseases such as multiple sclerosis);
- Monoclonal antibodies with activity against components of the immune system.
The EMA has been in discussion with developers of 34 potential COVID-19 vaccines (figure correct as of 15th June 2020). Vaccine development timelines are difficult to predict. Based on past experience, EMA estimates that it might take at least until the beginning of 2021 before a vaccine against COVID-19 is ready for approval and available in sufficient quantities to enable widespread use.
Global regulators discuss data requirements for phase 3 trials of COVID-19 vaccines
Under the umbrella of the International Coalition of Medicines Regulatory Authorities (ICMRA), international regulators discussed COVID-19 vaccine development and the necessary evidence required for regulatory decision-making at the second regulatory workshop on COVID-19 vaccines. The meeting was jointly organised by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) on 22nd June 2020.
During the workshop, global regulators focused on requirements for non-clinical and clinical data from early phase studies that are needed before proceeding with advanced (phase 3) clinical trials with COVID-19 vaccine candidates in humans. They exchanged views on key aspects, such as eligibility criteria for inclusion of diverse populations, primary endpoints and other methodological considerations related to the design of phase 3 clinical trials.
Meeting participants agreed that regulatory convergence, to the extent possible, on certain key aspects of phase 3 clinical trial designs will help developers to generate robust evidence on the quality, safety and efficacy of potential COVID-19 vaccines that meets the needs of regulators around the globe. This is critical for expediting and streamlining global development and authorisation of vaccines against COVID-19.
Global regulators work towards alignment on policy approaches and regulatory flexibility during COVID-19 – update #4
The ICMRA convened its regular virtual meeting of regulators from around the world on 12th June 2020 to discuss high-level policy issues and regulatory approaches to ensure a coordinated response to the ongoing COVID-19 pandemic.
They agreed that a clear distinction between exploratory clinical trials and confirmatory studies for the treatment of COVID-19 is critical for clinical trial prioritisation. They reiterated that the research community should pool resources into large, well-designed, randomised clinical trials to determine which investigational or repurposed medicines would be safe and effective for the treatment or prevention of COVID-19. They discussed the use of global COVID-19 clinical trial master protocols to accelerate the development and approval of potential treatments and vaccines against COVID-19.
Regulators also shared concerns about the discontinuation of clinical trials globally and the growing number of underpowered studies that might not generate the robust data required for regulatory decision-making.
European Commission, EMA and FDA agree new priorities to strengthen their collaboration on medicines
Senior officials from the EC, EMA and the FDA held their 2020 bilateral regulatory dialogue meeting on 18th and 19th June 2020. During this virtual two-day meeting, the authorities reviewed their ongoing joint initiatives, discussed strategic priorities for the coming years and identified areas where their already close collaboration can be further strengthened. The two agencies have now almost daily interactions with the aim to better align, and advance scientific and regulatory excellence worldwide.
In the context of the COVID-19 pandemic, the EC, EMA and FDA have further intensified their collaboration through regular interactions, notably under the umbrella of the ICMRA. Given the medical emergency presented by COVID-19 and the importance of international cooperation to tackle this global crisis, the topic was high on the agenda of the bilateral meeting.
Topics discussed included:
- Sharing experience and common challenges in facilitating the development, review and availability of COVID-19 vaccines;
- Cooperation on individualised/bespoke therapies for ultrarare diseases to jointly address their scientific and regulatory challenges;
- Agreement to collaborate on observational research in COVID-19 as a model, specifically on vaccines surveillance, building international cohorts, and the use of medicines in pregnant women with COVID-19;
- Next milestones in Mutual Recognition Assessments (MRA) following GMP inspections include expansion to veterinary medicines and the consideration to include vaccines and plasma-derived products by July 2022;
- Orphan and paediatric medicines: information sharing on initiatives and discussion on possible cooperation in the area of data analysis for the characterisation of rare diseases.
The US Food and Drug Administration (FDA)
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public Health Emergency
On 3rd June 2020, the FDA again updated their guidance on the conduct of clinical trials during the coronavirus pandemic.
The updates included the following:
- Inclusion of an index of the Q&A;
- Q10 included more information regarding if alternative methods are used to collect informed consent, the resulting documents or photographs or certified e-copies should be collected and retained appropriately;
- Q12 updated response with extended detail regarding the amendment of protocols to include remote Clinical Outcome Assessments (COA);
- Q23 – New question added, “What considerations apply to the electronic systems used to generate electronic signatures on clinical trial records, including informed consent documents, during the COVID-19 public health emergency?”. In brief, they must comply with 21 CFR Part 11.
Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency Guidance for Industry
The FDA posted the above guidance on 16th June 2020 to provide recommendations on statistical considerations to address the impact of COVID-19 on meeting trial objectives for clinical trials conducted during the duration of the COVID-19 public health emergency.
The discussion includes sections on Trial Integrity and Trial Mitigation and Analysis Strategies.
Modifications to the analysis of the primary or key secondary endpoints should be reflected in an updated statistical analysis plan before locking the database and before any modifications to unblinded interim analyses. In addition, the FDA recommends that sponsors consult with them when considering protocol changes and changes to the statistical analysis plan that may impact the analysis and interpretation of these endpoints.
Institutional Review Board (IRB) Review of Individual Patient Expanded Access (“compassionate use”) Requests for Investigational Drugs and Biological Products During the COVID-19 Public Health Emergency
On the 2nd June 2020, the FDA issued guidance on the above topic for IRBs and Clinical Investigators, as the COVID-19 public health emergency has led to a substantial increase in the number of requests by physicians seeking to treat their patients with investigational drugs under FDA’s individual patient expanded access pathway. This pathway, sometimes called “compassionate use,” allows a patient with a serious or immediately life-threatening disease or condition to gain access to an investigational drug or biological product when there is no comparable or satisfactory alternative therapy; the potential patient benefits justifies the potential risks to the patient; and the requested use will not interfere with clinical investigations that could support marketing approval.
Recommendations given in this guidance are intended to assist IRBs in complying with the requirements in 21 CFR Part 56 when reviewing individual patient expanded access requests. They include establishing documented procedures, focussing on the risk/benefit to the individual patient, preparing a thorough patient history and treatment plan to be included in the Form FDA 3926 or in another document, to assess the qualifications of the submitting physician, confirm adequate provisions for paediatric patients, and adequate wording in informed consents.
Six warning letters were issued by the FDA regarding either Adulterated or Unapproved and Misbranded Products Related to Coronavirus Disease 2019 (COVID-19), between the 15th and the 17th June 2020. The firms involved were KBMO Diagnostics LLC, North Isle Wellness Center, Project 1600 Inc., Medakit Ltd, antibodies check, and Sonrisa Family Dental dba mycovidtest19.
Some examples of the claims included statements such as ““BLUBLOCK . . . Shield Against CoronaVirus . . . It’s [sic] key ingredient is Methylene Blue. Methylene Blue works by producing a hydrogen peroxide burst within the blood to kill the Coronavirus (COVID-19) on contact.” False claims of FDA approval and misuse of the FDA logo were noted.
Other News Updates
Medicines and Healthcare products Regulatory Agency (MHRA)
Good Clinical Practice Symposium 2020
On 16th June 2020, Rachel Mead, MHRA GCP Inspector published a summary of the MHRA Good Clinical Practice Symposium 2020.
Between 11 and 14 February 2020, the MHRA hosted a week-long series of events concluding with the second joint MHRA GCP and US Food and Drug Administration (FDA) event which was the first one hosted by the MHRA in the UK. The event focussed on the next steps in relation to data integrity for both GCP and bioequivalence (BE) inspections, providing both MHRA and FDA perspectives in all sessions. Sessions included International Collaboration, Sponsor Oversight: International Perspective, eSource (including Electronic Health Records), Protocol Deviations: Identification, Impact, and Reporting, and Challenges in Ensuring Data Quality in Novel Clinical Trial Design.
European Medicines Agency (EMA)
EMA Annual Report 2019 Published
On the 15th June 2020, the EMA released its 2019 annual report and for the first time, the report is available in a digital version as well as pdf.
In 2019 the EMA received a record number of requests for scientific advice. The numbers of applications for marketing authorisation increased to 117 and the EMA recommended 66 new medicines for marketing authorisation, including a 1st vaccine against Ebola. The EMA continued to closely monitor the safety of medicines on the market and take action when needed. The product information for 405 centrally authorised medicines was updated on the basis of new safety data.
Regarding inspections and compliance, 137 GCP inspections were requested by the CHMP in 2019. the highest number of GCP inspections was conducted in the USA (a total of 16 critical, 117 major and 53 minor findings made), followed by the EU/EEA (9 critical, 109 major and 43 minor findings) and the Middle East/Asia/Pacific regions. The fewest findings were observed equally in Eastern EU (non-EEA) and Australia/New Zealand, with 0 critical, 4 major and 8 minor findings from each region. A discussion on the types of findings was not provided.
Canada – Confidentiality Arrangement including Personal Data
An update to the confidentiality arrangement between the EMA, the EC and Health Canada published on 16th June 2020 included references to personal data legislation and the permanent validity of the arrangement.
The confidential information that EMA and Health Canada can share includes:
- Applications for scientific advice, orphan designation, marketing authorisation and post-authorisation variations;
- Applications for agreement of paediatric investigation plans;
- GCP inspections for specific products and GCP inspection reports available to EMA or the European Commission;
- GMP inspections;
- Pharmacovigilance data, particularly in relation to adverse drug reactions, as well as safety concerns arising from periodic safety update reports and post-authorisation obligations and commitments, and inspection reports;
- All legislation and guidance documents;
- Information technology systems supporting regulatory processes.
Issue Number: RN2006
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