Guidance Documents on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic Released in March

European Medicines Agency (EMA), Food and Drug Administration (FDA) and Medicines and Healthcare products Regulatory Agency (MHRA) issued their guidance on the management of clinical trials during the pandemic this month:

EMA Guidance, 20th March 2020

The European Commission (EC), the EMA and national Head of Medicines Agencies (HMA) have published recommendations for sponsors on how to manage the conduct of clinical trials in the context of the COVID-19 pandemic.

This guidance includes a harmonised set of recommendations to ensure the utmost safety of trial participants across the European Union while preserving the quality of the data generated by the trials. It also advises how to communicate changes to the authorities.

There is specific advice on the initiation of new clinical trials for treatments of COVID-19, and in particular, on the need for large, multinational trial protocols.

The guidance requires sponsors and investigators to take into account specific national legislation and guidance which complement the EMA guidance, or, with respect to particular topics, may take priority over the guidance.

https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf

https://www.ema.europa.eu/en/news/guidance-sponsors-how-manage-clinical-trials-during-covid-19-pandemic

FDA Guidance, 18th March 2020

The FDA issued guidance for Industry, Investigators, and Institutional Review Boards to provide general considerations to assist sponsors in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during the COVID-19 pandemic. FDA recognizes protocol modifications may be required, and there may be unavoidable protocol deviations due to COVID-19 illness and/or COVID-19 control measures.  Robust efforts by sponsors, investigators, and Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) to maintain the safety of trial participants and study data integrity are expected, and such efforts should be documented.

https://www.fda.gov/media/136238/download

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-pandemic?utm_campaign=SBIA%3A%20Coronavirus%20%28COVID-19%29%20Update%3A%20FDA%20Issues%20Guidance%20for%20Conducting%20Clinical%20Trials&utm_medium=email&utm_source=Eloqua

MHRA Guidance, 19th Mar 2020

Managing Clinical Trials during Coronavirus (COVID-19) Guidance was first published by the MHRA on 19th March 2020 and last updated on 24th Mar 2020. This guidance advises those involved in clinical trials on specific issues which may arise as a result of COVID-19, and what they are required to do. The MHRA have issued separate guidance on clinical trials applications for Coronavirus (COVID-19).

The contents of the guidelines are as follow:

  • Submitting paperwork for trials which have been halted
  • Restarting a trial after it has been halted
  • Providing investigational medicinal product (IMP) to trial participants
  • Remote monitoring for trials
  • Replacing in-person visits with phone calls
  • Reducing the number of participant monitoring visits
  • ‘Dear Investigator’ Letters
  • Reporting of serious adverse events (SAEs), and submission of annual safety reports (DSURs) and end of trial notifications
  • Protocol deviations and serious breaches
  • Protocol waivers
  • Subject safety
  • Signatures
  • Help from the MHRA

https://mhrainspectorate.blog.gov.uk/2020/03/20/mhra-guidance-on-coronavirus/

https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19#history

EMA: Call to pool research resources into large multi-centre, multi-arm clinical trials to generate sound evidence on COVID-19 treatments

EMA’s Human Medicines Committee (CHMP) has published a statement urging the EU research community to prioritise large randomised controlled studies1 because they are most likely to generate the conclusive evidence needed to enable rapid development and approval of potential treatments of COVID-19. The statement promotes a harmonised approach to data collection and a robust methodology for COVID-19 clinical trials across the EU to make best use of the available supply of investigational agents. It emphasises the need to include all EU countries in these trials.

At the moment, there are no approved medicines to protect from or treat COVID-19.

The CHMP has discussed the ongoing outbreak and emphasises the critical need for robust data to determine which investigational or repurposed medicinal products would be safe and effective for the treatment of COVID-19. The Committee is concerned that clinical trials with a small number of participants or compassionate use programmes might not generate the data required to draw firm conclusions on the effects of a given therapeutic and give appropriate advice to healthcare professionals and patients.

EMA is ready to support medicine developers with all available regulatory tools to advance and expedite the development of effective measures to fight and prevent the spread of COVID-192.

1https://www.ema.europa.eu/en/documents/other/call-pool-eu-research-resources-large-scale-multi-centre-multi-arm-clinical-trials-against-covid-19_en.pdf

2https://www.ema.europa.eu/en/news/call-pool-research-resources-large-multi-centre-multi-arm-clinical-trials-generate-sound-evidence

FDA Update on coronavirus

  • The FDA publishes ‘Daily Roundups’ to announce actions taken in its ongoing response effort to the COVID-19 pandemic. The actions taken outlined in the release dated 25th March 2020 and 26thMarch 2020 included1,2,10:
  • In response to the demand for alcohol-based hand sanitizers and their active ingredient, alcohol, the FDA issued another guidance for industry about hand sanitizers, “Temporary Policy for Manufacture of Alcohol for Incorporation Into Alcohol-Based Hand Sanitizer Products During the Public Health Emergency (COVID-19) Guidance for Industry”3.
  • The FDA posted questions and answers related to consumer use of hand sanitizer during the COVID-19 public health emergency10.
  • The FDA added hydroxychloroquine sulfate to category 1 under the Interim Policy on Compounding Using Bulk Drug Substances Under Section 503B of the Federal Food, Drug, and Cosmetic Act1.
  • The FDA issued an emergency use authorization for ventilators, anesthesia gas machines modified for use as ventilators, and positive pressure breathing devices modified for use as ventilators (collectively referred to as “ventilators”), ventilator tubing connectors, and ventilator accessories4.
  • Diagnostics update to date: During the COVID-19 pandemic, the FDA has worked with more than 220 test developers who have said they will be submitting applications to make tests that detect the virus. To date, 17 emergency use authorizations5 have been issued for nation-wide use. Additionally, under COVID-19 laboratory developed test policy6, the FDA has been notified by more than 100 laboratories.
  • the FDA issued an immediately in effect guidance: Enforcement Policy for Face Masks and Respirators During the Coronavirus Disease-2019 (COVID-19) Public Health Emergency10,11.

1https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-25-2020

2https://www.fda.gov/

3https://www.fda.gov/media/136390/download

4https://www.fda.gov/media/136423/download

5https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ventilators

6https://www.fda.gov/media/135659/download

10https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-march-26-2020?utm_campaign=032620_PR_Coronavirus%20%28COVID-19%29%20Update%3A%20Daily%20Roundup–March%2026%2C%202020&utm_medium=email&utm_source=Eloqua

11https://www.fda.gov/media/136449/download

  • FDA published “Enforcement Policy for Non-Invasive Remote Monitoring Devices Used to Support Patient Monitoring During the Coronavirus Disease 2019 (COVID-19) Public Health Emergency” guidance to provide a policy to help expand the availability and capability of non-invasive remote monitoring devices to facilitate patient monitoring while reducing patient and healthcare provider contact and exposure to COVID-19 during this pandemic7,8.

7https://www.fda.gov/media/136290/download

8https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-non-invasive-remote-monitoring-devices-used-support-patient-monitoring-during

  • As per publication on 19th March 2020, the FDA continues to facilitate development of treatments. Work is continuing with the public and private sector to ensure the availability of potentially safe and effective life-saving drugs to patients who are in desperate need, including those infected with COVID-19. The FDA has been working closely with other government agencies and academic centers that are investigating the use of the drug chloroquine, which is already approved for treating malaria, lupus and rheumatoid arthritis, to determine whether it can be used to treat patients with mild-to-moderate COVID-19 to potentially reduce the duration of symptoms, as well as viral shedding, which can help prevent the spread of disease. Studies are underway to determine the efficacy in using chloroquine to treat COVID-199.

9https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-continues-facilitate-development-treatments?utm_campaign=031920_PR_Coronavirus%20%28COVID-19%29%20Update%3A%20Chloroquine&utm_medium=email&utm_source=Eloqua

  • FDA focuses on safety of regulated products while scaling back domestic inspections. On 18th March 2020, the FDA announced that for the health and well-being of the FDA staff and those who conduct inspections for the agency under contract at the state level, and because of industry concerns about visitors, the FDA has temporarily postponed all domestic routine surveillance facility inspections. These are facility inspections the FDA traditionally conducts every few years based on a risk analysis. Importantly, all domestic for-cause inspection assignments will be evaluated and will proceed if mission-critical. The FDA will continue to respond to natural disasters, outbreaks and other public health emergencies involving FDA-regulated products12.

12https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-focuses-safety-regulated-products-while-scaling-back-domestic?utm_campaign=031820_PR_Coronavirus%20%28COVID-19%29%20Update%3A%20FDA%20Focuses%20on%20Safety%20of%20Regulated%20Products&utm_medium=email&utm_source=Eloqua

MHRA guidance on Coronavirus (COVID-19)

In addition to the Managing Clinical Trials Guidance During Coronavirus and Clinical Trials Applications for Coronavirus, the MHRA produced also other guidance for industry covering the Coronavirus (COVID-19) outbreak1:

  • Inspections:
    • “New arrangements for MHRA Good Practice (GxP) inspections due to Coronavirus (COVID-19)”2. The MHRA have decided to conduct only essential on-site Good Practice (GxP) inspections of Laboratories, Clinical Trials, Manufacturing, Distribution and Pharmacovigilance until further notice. Other MHRA inspections will be deferred to a later date.
  • Medical Devices:
    • “Regulatory status of equipment being used to help prevent Coronavirus (COVID-19)”7. There are different regulations which apply to devices and equipment including hand gels and PPE (personal protective equipment). The guidance contains information regarding antimicrobial hand sanitisers and gels, face masks and gloves.
    • “Exemptions from Devices regulations during the Coronavirus (COVID-19) outbreak”3
    • “How to place a Coronavirus (COVID-19) test kit on the market”4.
    • “Specification for ventilators to be used in UK hospitals during the Coronavirus (COVID-19) outbreak”5.
  • Medicines Regulations:
    • “Guidance for Manufacturers Specials licence holders on ‘packing down’ medicines during the Coronavirus (COVID-19) outbreak”. Given the current COVID-19 situation, the MHRA are mindful that to ensure supply at the local level, some Manufacturers Specials holders may be requested to pack down for distribution to community (retail) pharmacies. The MHRA does not object to this activity during the COVID-19 outbreak provided that certain requirements are fulfilled and highlights that this guidance only applies during the COVID-19 outbreak6.

1https://www.gov.uk/government/collections/mhra-guidance-on-coronavirus-covid-19

2https://www.gov.uk/government/news/new-arrangements-for-mhra-good-practice-gxp-inspections-due-to-coronavirus-covid-19–2

3https://www.gov.uk/guidance/exemptions-from-devices-regulations-during-the-coronavirus-covid-19-outbreak

4https://www.gov.uk/government/publications/regulatory-approval-for-coronavirus-covid-19-test-kits

5https://www.gov.uk/government/publications/specification-for-ventilators-to-be-used-in-uk-hospitals-during-the-coronavirus-covid-19-outbreak

6https://www.gov.uk/guidance/guidance-for-manufacturers-specials-licence-holders-on-packing-down-medicines-during-the-coronavirus-covid-19-outbreak

7https://www.gov.uk/guidance/regulatory-status-of-equipment-being-used-to-help-prevent-coronavirus-covid-19

Other MHRA COVID-19 related news

Chloroquine and Hydroxychloroquine not licensed for Coronavirus (COVID-19) treatment

As published on 25th March 2020, Chloroquine and hydroxychloroquine are not licensed to treat COVID-19 related symptoms or prevent infection. Clinical trials are ongoing to test chloroquine and hydroxychloroquine as an agent in the treatment of COVID-19 or to prevent COVID-19 infection. These clinical trials are still not completed, so no conclusions have been reached on the safety and effectiveness of this medicine to treat or prevent COVID-19.

https://www.gov.uk/government/news/chloroquine-and-hydroxychloroquine-not-licensed-for-coronavirus-covid-19-treatment

Ibuprofen use and Coronavirus (COVID-19)

The MHRA released a government response on 20th March 2020, on Ibuprofen use and Coronavirus. There is currently no strong evidence that ibuprofen can make Coronavirus (COVID-19) worse. However, the publication states that patients who have confirmed COVID-19, or believe they have COVID-19, should take paracetamol in preference to ibuprofen. Those currently advised to use ibuprofen by their healthcare professional should not stop using them.

There is some debate suggesting non-steroidal anti-inflammatory medications (NSAIDs) may increase complications from simple acute respiratory infections or slow recovery. The product information of many NSAIDs already contains warnings that their anti-inflammatory effects may hide the symptoms of a worsening infection. However, the evidence is not conclusive, as the MHRA highlights.

In view of the current lack of research the Commission on Human Medicines (an expert advisory body of MHRA) and The National Institute for Health and Care Excellence (NICE) have been asked to review the evidence.

https://www.gov.uk/government/news/ibuprofen-use-and-covid19coronavirus

Coronavirus: global crackdown sees a rise in unlicenced medical products related to COVID-19

News dated 19th March 2020. Operation Pangea XIII took place from March 3 to 10 and involved police, customs and health regulatory authorities from 90 countries, all aiming to prevent the activity of illicit online sales of medicines and medical products. Counterfeit face masks and unauthorised antiviral medication were all seized under the operation. This year’s operation identified a disturbing trend of criminals who are taking advantage of the COVID-19 outbreak by exploiting the high market demand for personal protection and hygiene products.

Globally, 2,000 online advertisements related to COVID-19 were found and more than 34,000 unlicensed and fake products, advertised as “corona spray”, “coronavirus medicines” or, “coronaviruses packages” were seized. Fake medicines included anti-depressants, erectile dysfunction tablets, painkillers and anabolic steroids all seized by officers from the MHRA and UK Border Force. The seizures were part of Interpol’s globally coordinated Operation Pangea targeting the illegal sale online of fake and illegal medicines and devices.

The MHRA provides a safety advice when buying medicines: be careful when buying medicines online and do not self-prescribe.

https://www.gov.uk/government/news/coronavirus-global-crackdown-sees-a-rise-in-unlicenced-medical-products-related-to-covid-19

MHRA services during the Coronavirus (COVID-19) response

Publication dated 20th March 2020 states that there should be a little to no impact on contacting MHRA. The MHRA is available through telephone and email.

https://www.gov.uk/government/news/mhra-services-during-the-coronavirus-covid-19-response

EMA Management Board – highlights of March 2020 meeting

On 20th March 2020 EMA released a summary of their virtually held Meeting March. Some meeting highlights are as follows1,2:

  • EMA has now invoked its Business Continuity Plan (BCP) to allow the Agency to manage the pandemic. The plan aims to safeguard the Agency’s core activities and to ring-fence resources that are needed to deal with COVID-19. Despite the reduction in the physical presence of staff at the Agency’s premises, EMA’s core activities in relation to the authorisation and supervision of medicines continue in phase 1 of the EMA COVID-19 BCP.
  • The Board adopted EMA’s annual report for 2019. Altogether, EMA recommended 66 medicines for marketing authorisation in 2019. Of these, 30 had a new active substance: seven were orphan medicines, and one (Zynteglo) was an advanced-therapy medicine for the treatment of a rare inherited blood condition that causes severe anaemia. A conditional marketing authorisation was granted for the first vaccine against the Ebola virus. Publication of the 2019 report, as well as a new digital version, is planned towards the end of April 2020.
  • Update on the presence of nitrosamine impurities in medicines. The Board was updated on the exercise undertaken by EU authorities to determine what lessons can be learned from the presence of nitrosamines in sartans, which came to light in mid-2018. A draft report was presented to the Board. An external targeted consultation with stakeholders is planned, after which the final recommendations will be submitted for endorsement by the Board and by HMA and published later in the year.
  • Update on the development of the Clinical Trials Information System (CTIS) for the EU Clinical Trials The Management Board endorsed the CTIS audit methodology enabling the process for the selection of the supplier for the audit of the system to commence. The audit is planned to begin in December 2020.
  • The Board endorsed the Regulatory Science Strategy to 20253, the plan for advancing engagement with regulatory science over the next few years. This process involved several rounds of consultation and two major workshops with academia, scientific organisations, patients, healthcare professionals, industry and partners. The final strategy and the public consultation analysis will be published at the end of March. The strategy will be a key pillar of the work of the Agency and the network in the coming years and will feed into the development of the European medicines network strategy to 2025.

1https://www.ema.europa.eu/en/news/ema-management-board-highlights-march-2020-meeting

2https://www.ema.europa.eu/en/documents/agenda/ema-management-board-highlights-march-2020-meeting_en.pdf

3https://www.ema.europa.eu/en/about-us/how-we-work/regulatory-science-2025

FDA New Guidance on Competitive Generic Therapies

The Guidance was published as final in March 2020 and provides a description of the process that applicants should follow to request designation of a drug as a competitive generic therapy (CGT) and the criteria for designating a drug as a CGT. It also includes information on the actions FDA may take to expedite the development and review of abbreviated new drug applications (ANDAs) for drugs designated as CGTs. Finally, it provides information on how FDA implements the statutory provision for a 180-day exclusivity period for certain first approved applicants that submit ANDAs for CGTs.

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/competitive-generic-therapies?utm_campaign=SBIA%3A%20FDA%20publishes%20guidance%20for%20industry%3A%20Competitive%20Generic%20Therapies&utm_medium=email&utm_source=Eloqua

https://www.fda.gov/media/136063/download

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