Regulatory Surveillance Summary | May 2020
By Laurel Hacche and Debra Cortner, SQA Associates
Health Canada Regulations and Guidances
The COVID-19 pandemic has led to a global search for therapies to treat, diagnose, mitigate, or prevent the infection. Before new therapies can be made available to Canadians, they must be shown to be safe and effective, and clinical trials are a critical part of that process. As of the time of this announcement, Health Canada has approved 37 clinical trials for potential COVID-19 therapies and vaccines. To accelerate these efforts, the Minister of Health has authorized the following changes for a more flexible process for clinical trials related to COVID-19, without compromising the safety of participants or the reliability of trials’ findings:
- Allow a wider range of health professionals, such as nurse practitioners, to be involved in running clinical trials. Under current regulations, only physicians and dentists can conduct clinical trials for drugs;
- Allow a wider range of investigators, such as physicians, to be involved in running clinical trials for medical devices. Under current regulations, only manufacturers can conduct clinical trials for medical devices;
- Reduce the burden associated with labeling and record-keeping requirements for clinical trials involving drugs that are already marketed for other indications and are being studied to treat COVID-19;
- Enable multiple-stream clinical trials to continue, even when one stream has been stopped; and
- Enable more clinical trials by allowing trials where direct interaction with the participant is not feasible (e.g., when participants who live in remote locations are unable to travel).
Health Canada has received reports that fraudulent and uncertified N95 respirators falsely claiming to protect consumers against COVID-19 are being illegally sold to consumers online and in some stores. In Canada, N95 respirators are regulated by Health Canada as Class I medical devices and are manufactured or imported by companies that hold a Medical Device Establishment License. They are also certified by the U.S. National Institute for Occupational Safety and Health (NIOSH). Fraudulent or unauthorized N95 masks may not meet the same performance measures required by the NIOSH N95 standard and, as a result, may not properly protect consumers from COVID-19. When worn properly, NIOSH-certified N95 respirators are designed to secure a close facial fit and reduce the risk of inhaling hazardous airborne particles and aerosols. The “N95” designation means that when subjected to careful testing, the respirator blocks at least 95% of very small test particles, such as pathogens. For a depiction of the NIOSH symbol, refer to the NIOSH website. It is illegal to sell or advertise health products that make false or misleading claims. The Department takes this issue seriously and will use all available tools to stop these activities. Health Canada monitors websites and takes action when false claims and/or unauthorized products are identified and is working with online retailers to ensure that these products are removed from their websites. Health Canada is also working with other government departments and agencies, such as the Competition Bureau, the Public Health Agency of Canada, and the Canada Border Services Agency to address the issue of false and misleading claims related to COVID-19 and will continue to take compliance and enforcement actions to protect the health and safety of Canadians.
Health Canada warned Canadians about the potential health risks of making and using homemade hand sanitizers, as homemade recipes and products are becoming increasingly common online. The concentration of alcohol in many of the homemade hand sanitizers may not be high enough to kill the coronavirus that causes COVID-19. Homemade formulas may also present other health risks, such as skin irritation, increased sensitivity, or allergies. Health Canada recommends only using hand sanitizers that have been authorized for sale in Canada. Product labels for authorized hand sanitizers will have either a Natural Product Number (NPN) or Drug Identification Number (DIN).
Medicines & Healthcare Products Regulatory Agency (MHRA)
The MHRA is working closely with the Department of Health and Social Care (DHSC) and other healthcare partners on COVID-19. Prioritized work includes:
- Supporting and authorizing the development of vaccines
- Clinical trials of new medicines
- Managing the supply of medicines and healthcare products
The MHRA also provides information to patients, manufacturers, and healthcare professionals through established information channels and alert systems. The National Institute for Biological Standards and Control (NIBSC), a center of the MHRA, also plays a major role in assuring the quality of biological medicines, worldwide. The NIBSC has developed a portfolio of reference and research reagents to support areas of diagnostics, vaccine development, and research on COVID-19, and has called upon the scientific community to build standardization into the pandemic response. The Clinical Practice Research Datalink (CPRD), another agency center, is making COVID-19 research a top priority by fast-tracking protocols for COVID-19 research. All approved study protocol summaries are published within 72 hours to ensure transparency and to help avoid unnecessary duplication. The British Pharmacopoeia (BP) has published a statement on its products and services during the outbreak, including some actions for any BP Chemical Reference Substance (BPCRS) customers who are ordering any substances classified as controlled drugs or precursor chemicals. The BP has also published a statement on offering free access to supportive pharmacopeial texts to users at no cost. The MHRA Inspectorate blog has several posts covering the approach taken for clinical trials and advice on other areas like remote working.
The MHRA has given the first positive scientific opinion under the Early Access to Medicines Scheme (EAMS) for use of Gilead’s remdesivir. This step will support the use of remdesivir in the treatment of adults and adolescents hospitalized with severe coronavirus (COVID-19) infection who meet additional clinical criteria. The EAMS was set up by the MHRA to give patients with life-threatening or seriously debilitating conditions access to medicines that are not yet licensed, but when there is a clear, unmet medical need. Following expert advice from the Commission on Human Medicines and the Expert Working Group on COVID-19, the MHRA has delivered this scientific opinion after a rigorous evaluation of the benefit-risk balance of the medicine, based on the data available. This scientific opinion does not replace the normal licensing procedures for medicines but supports prescribers and patients to make a decision on whether to use the medicine before its license is approved. As part of the scientific opinion, a framework to collect safety data and manage risks will be implemented. Remdesivir’s current use in the UK will be for patients in cases of high unmet medical need determined by a physician through the EAMS, where it will be provided to the National Health Services (NHS) free of charge by Gilead throughout the EAMS period. It will also continue to be used in clinical trials. Several clinical trials to evaluate Remdesivir and its possible effects on patients with COVID-19 have already been approved by the MHRA and are ongoing in the UK.
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances
The ICH S11 Guideline on Nonclinical Safety Testing in Support of Development of Pediatric Medicine reached Step 4 of the ICH Process in April 2020. This Guideline provides direction on the nonclinical safety studies important to support a pediatric development program. It recommends standards for the conditions under which nonclinical juvenile animal testing is considered informative and necessary to support pediatric clinical trials, and also provides guidance on the design of the studies. Streamlining drug development and applying higher scientific rigor while minimizing the unnecessary use of animals will be achieved with the implementation of this new Harmonized ICH Guideline.
The United States FDA is organizing a free two-day Pan-American-focused public web conference on Thursday, 04 June 2020, and Friday, 05 June 2020, from 10:00 am to 1:00 pm EDT, to learn more about stakeholder experiences with the ICH Good Clinical Practice Guideline, ICH E6. This stakeholder engagement web conference will inform the discussions of the ICH Expert Working Group (EWG), which is tasked with updating the Guideline and making it more responsive to advances in clinical trial design and conduct. Members of the EWG will provide an overview of the ongoing work to update the Guideline and will then hear from multiple stakeholders on their experiences with ICH E6(R2).
The European Federation for Cosmetic Ingredients (EFfCI)
The cosmetic industry has been deeply affected by the COVID-19 pandemic due to restrictions on movement, issues with having enough materials and people to be able to deliver product, and coping with uncertainty. Members may not be able to attend planned events. In response, the EFfCI has postponed or canceled industry events including conferences, exhibitions, and seminars. Many will not be rescheduled during 2020.
In a document intended to be followed by EFfCI Registered Certification Bodies, the EFfCI acknowledges that conducting an EFfCI GMP audit while countries are in lockdown as a result of the COVID-19 pandemic crisis may not be possible. The document describes alternative options when a physical audit is not permitted, to maintain or renew GMP Certification of Cosmetic Ingredient manufacturers and distributors. The document indicates the conditions and time periods that are acceptable to postpone a re-certification or surveillance audit or to replace it with a remote audit. The Certification Body is responsible for informing the EFfCI about their decision to either postpone the on-site audit or conduct a remote certification audit, before the audit is completed. Considerations are set out in the document. Procedures for the organization of the audit, confidentiality agreement, risk assessment for allowing a remote audit, and how to conduct the audit are described.
European Medicines Agency (EMA)
The European Medicines Agency has published an overview of how the Agency will accelerate regulatory procedures so that marketing authorizations of safe, effective, and high quality COVID-19-related medicines can be granted as soon as possible. According to Executive Director Guido Rasi, these rapid approvals will only be possible if applications are supported by robust and sound scientific evidence of positive benefit-risk balance.
The EMA, Good Clinical Practice Inspectors Working Group (GCP IWG); the Clinical Trials Facilitation and Coordination Group (CTFG), a working group of the Heads of Medicines Agency (HMA); the Clinical Trials Expert Group (CTEG), a working group of the European Commission representing Ethics Committees and the National Competent Authorities (NCA); and the European Commission (EC) acknowledge the impact of COVID-19 on the health system and broader society, as well as the impact it may have on clinical trials and trial participants. Extraordinary measures may need to be implemented and trials adjusted due, among others things, to trial participants being in self-isolation or quarantine, having limited access to public places (including hospitals) due to the risk of spreading infection, and healthcare professionals being committed to critical tasks. The feasibility and immediate necessity of starting a new clinical trial should be critically assessed by sponsors in close collaboration with other relevant parties, in particular the investigators. Additional risks to trial participants should be addressed in the benefit-risk section of the protocol, along with risk mitigation measures. Sponsors and investigators should consider in their risk assessment whether the following measures could be the most appropriate during COVID-19:
- Conversion of physical visits into phone or video visits, postponement or complete cancellation of visits to ensure that only strictly necessary visits are performed at sites
- A temporary halt of the trial at some or all trial sites
- Interruption or slowing down of recruitment of new trial participants – the feasibility of including new trial participants in an ongoing trial needs to be critically assessed
- Extension of the duration of the trial
- Postponement of trials or of activation of sites that have not yet been initiated
- Closing of sites: When it is not feasible for a site to continue participation at all, the sponsor should consider if the trial site should be closed and how this can be done without compromising the rights, safety, and wellbeing of trial participants and data validity
- If unavoidable (it should be justified that this is a truly exceptional situation based on the personal benefit-risk ratio for the individual trial participant), transfer of trial participants to investigational sites away from risk zones, or closer to their home, to sites already participating in the trial, or new ones, could occur
There may be a need for critical laboratory tests, imaging, or other diagnostic tests to be performed (e.g., blood cell count, liver function test, X-ray, CT, MRI, ultrasonography, or ECG) for trial participant safety or the integrity of the trial. In the case that the trial participant cannot reach the site to have these performed, it is acceptable that laboratory, imaging, or other diagnostic tests be performed at a local laboratory or relevant clinical facility authorized or certified (as legally required nationally) to perform such tests routinely, if this can be completed within local restrictions for social distancing. The sites should inform the sponsor about such cases. Local analysis can be used for safety decisions. Sponsors are expected to continue safety reporting in adherence to EU and national legal frameworks (Directive 2001/20/EC; CT-3).
European Parliament – Device Update
On 17 April 2020, the European Parliament adopted the European Commission’s (EC) proposal to postpone the implementation of the Medical Devices Regulation (MDR) 2017/745 by 12 months. This urgently drafted proposal to delay the MDR is in response to the exceptional circumstances associated with the COVID-19 pandemic and the potential impact it may have had on the MDR implementation. The proposal now also has to be approved by the member states and published in the Official Journal of the European Union (OJEU) before it enters into force. This is expected to be completed by 26 May 2020. Once in force, the new Date of Application (DoA) for the MDR will be 26 May 2021. The one-year delay will bring some relief from the intense pressure on organizations, notified bodies, and competent authorities to complete the MDD/AIMDD transitions and early renewals before the 26 May 2020 deadline. However, despite the postponement of the DoA, the EC will continue to employ their resources on critical devices in the context of the COVID-19 pandemic and conformity assessments under the MDR to ensure effective implementation of Regulation. It is important to note that, although the DoA has been delayed by one year, the key deadline of 26 May 2024, when the Directive-based certificates issued by notified bodies become invalid, remains the same.