To help our clients navigate the coronavirus (COVID-19) crisis, Arnold & Porter has established a Coronavirus Task Force covering a wide range of issues and challenges. Subscribe to our "Coronavirus (COVID-19)" mailing list to receive our latest client Advisories and register for upcoming webinars.
Most recently, the European Medicines Agency (EMA) and the national EU authorities issued guidance to manage the conduct of clinical trials and the supply of medicinal products during the COVID-19 pandemic. Guidance is particularly important for all sponsors conducting studies and for companies supplying medicines in the EU.
Managing the impact on medicinal product supply chains
- The EMA updated guidance can be found on its website dedicated to COVID-19. The Agency anticipates that supply chains could be affected by the COVID-19 pandemic from the temporary closure of manufacturing sites in affected areas, restrictions on the import and export of medicines, and increased demand. The supply chain could also be affected by potential staff shortages resulting from illness, lockdowns, or quarantines.
- The EMA advises physicians not to prescribe quantities of medicines that exceed the normal duration of treatment. Pharmacies should ensure that patients receive only the "usual supply of medicines."
- Consistent with EU requirements, pharmaceutical companies are expected to ensure continued supply of medicinal products and to report any potential shortages to the authorities. In July 2019, the EMA published a related guidance document.
- The pharmaceutical industry is requested to assess both the risks arising from supply shortages and the resilience of the supply chain. In parallel, the EMA and the national authorities through Coordination Group on Mutual Recognition and Decentralised procedure (CMDh) are reviewing manufacturing information to identify medicines that are at most risk of supply shortages.
Conduct of Clinical Trials
On 20 March 2020, the EMA issued Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic. The guidance was developed in cooperation with an agreement by representatives of the competent authorities of the EU Member States and the European Commission., including the Clinical Trials Expert Group (CTEG) of the European Commission, the Clinical Trials Facilitation and Coordination Group (CTFG) of the Heads of Medicines Agencies (HMA), and the GCP Inspectors' Working Group coordinated by the EMA.
Sponsors should give careful consideration to the impact of COVID-19 on (a) ongoing trials, (b) new trial sites in an existing trial, (c) ongoing recruitment and continued involvement of participants in the trial, (d) and initiating new trials. In particular, Sponsors should take into account:
- EU Member States' national recommendations, including travel restrictions and confinement of trial participants and staff;
- Availability of trial staff to perform visits, enter data in the Case Report Form (CRF), notify of serious adverse events and, more generally, follow the protocol;
- Ability for the clinical trial sites to confirm eligibility and to conduct key safety assessments and trial evaluation;
- Changes to study protocols of ongoing
trials that may arise and their impact on:
- the overall safety, well-being, and best interests of the clinical trial patient (for example, in trials for patients with life-threatening or severely debilitating conditions, when trial subjects are required to stay on trial treatment or clinical trial patients who are in a risk group for COVID-19);
- the legitimate interest of the clinical trial sites in avoiding further burden in terms of time and staffing during the COVID-19 pandemic; and
- the impact of protocol changes on data interpretability.
The Guidance highlights the following points:
- Pragmatic and extraordinary measures
should be implemented and trials adjusted due to:
- trial participants being in self-isolation/quarantine;
- limited access to public places, including hospitals, due to the risk of spreading infections; and
- health care professionals' commitment to critical tasks and increased demands on the health service.
- Sponsors should consider:
- conversion of physical visits into phone or video visits, or the postponement or complete cancellation of such visits to ensure that only strictly necessary visits are performed at clinical trial sites;
- temporary halt of clinical trials at some or all trial sites or the closing sites of sites altogether;
- suspension or slowing down of recruitment of new trial participants;
- extension of the duration of the trial;
- postponement of trials or activation of sites that have not yet been initiated;
- if unavoidable, transfer of participants to investigational sites away from risk zones, or closer to their home, to sites already participating in the trial, or to new sites;
- in very exceptional circumstances,
initiation of new trial sites where no other solution exists for
the clinical trial patients:
- if there is an urgent need to open a new trial site for critical trial visits (such as outside the hospital), this may be implemented as an urgent safety measure first, with a substantial amendment application submitted later;
- implementation of critical laboratory tests, imaging or other diagnostic tests to be performed for patient safety, including such performed at local laboratories in proximity to the clinical trial patients homes;
- alternative procedures for obtaining the clinical trial patients' informed consent.
- Changes to trial conduct should be agreed with and communicated clearly to clinical trial sites;
- Changes to the distribution of the
investigational medicinal products may be implemented taking into
account: whether the products are appropriate for administration
and general storage at the patient's home; how the stability of
the product will be maintained during transit; how safe custody of
product will be ensured ;and how drug product accountability and
the evaluation of compliance to treatment (if appropriate) will be
managed. The changes could include implementation of:
- re-distribution of the investigational medicinal product between clinical trial sites;
- delivery of the investigational medicinal product directly to the patients' homes.
- Changes to the on-site monitoring activities, including suspension of these activities, remote monitoring, and implementing centralised monitoring mechanisms where possible;
- Implementation of protocol deviations in accordance with the sponsor's SOPs.
The EMA Guidance complements the guidance issued by the national authorities of the EU who are responsible for the authorisation and oversight of the conduct of clinical trials at a national level.
On 25 March 2020, the EMA published draft guidance addressing the actions that sponsors of ongoing clinical trials affected by COVID-19 are advised to take to help ensure the integrity of their studies and interpretation of study results while safeguarding the safety of trial participants as a first priority.
The draft guidance advises Sponsors to:
- pre-plan how systematic protocol deviations are to be captured to help distinguish between data affected by the deviations and unaffected data;
- generate in a pragmatic and feasible way sufficient information on pandemic-related measures and whether trial patients or trial conduct were affected;
- evaluate the implications on recruitment, loss of patients during the trial, ability to record data and ability to interpret the treatment effect in light of the pre-, during and post-pandemic measures phases.
This draft guidance is subject to a public consultation until 25 April 2020.
On 25 March 2020, the Belgian Federal Agency for Medicines and Health Products (FAMHP) issued a national Belgian Addendum to the EMA guidance. Consistent with other national policies, the FAMHP gives priority to clinical trial applications for treatments of COVID-19 and applications for substantial amendments to the protocols of ongoing existing clinical trials during the COVID-19 pandemic.
FAMHP further clarifies the following points:
- Sponsors are not permitted to ship the investigational medicinal product directly to patients. The product may be shipped from clinical trial sites to patients under the direct responsibility of principal investigators without any involvement from sponsors.
- The safety and rights of the patients must be protected (e.g., confidentiality) and the investigational medicinal product must be suitable for transport, storage and administration at home.
- The process of home drug-administration must be documented, including the training provided to patients for the self-administration or the involvement of a healthcare professional for the administration at the patient's home.
The FAMHP guidance also discusses the administrative steps for the notification of substantial amendments to the protocol and changes to the informed consent form related to the direct supply of the investigational product, but also temporary halts of the clinical trial, urgent safety measures and protocol deviations.
The FAMHP guidance also highlights that remote verification of data source is not permitted in Belgium as it violates the rights of the patients.
The general approach taken by the UK Medicines and Healthcare products Regulatory Agency (MHRA) is similar to that adopted by the EU. The MHRA is working closely with Department of Health and Social Care (DHSC) and other healthcare partners on matters concerning COVID-19. The MHRA is prioritising work including supporting and authorising the development of vaccines; clinical trials of new medicines; and managing the supply of medicines and healthcare products.
The MHRA has indicated that it will be as flexible and pragmatic as possible with regard to regulatory requirements for clinical trials during the COVID-19 pandemic. It also recognises that clinical trial resource may be absent or redeployed from research activities and regulatory affairs towards front-line care. That said, the MHRA emphasises the first priority should be the safety of trial participants and this will remain the Agency's focus.
If a trial has been halted due to issues related to COVID-19, sponsors will not normally need to inform the MHRA. The trial master file should include a note that the trial was halted and the reasons for doing so. If a halt is due to the following scenarios, then the MHRA should be informed:
- A direct participant safety issue, especially if there is the potential to impact other trials;
- A medicine supply issue, as the MHRA can escalate to DHSC. Sponsors are required to inform MHRA of this directly by phone or email rather than an amendment form.
If the restart of the study does not involve any substantial changes to the Clinical Trial Authorisation, then a substantial amendment notification to MHRA will not be necessary. If changes do need to be made to protect participant safety moving forward, then this should be submitted as a substantial amendment according to the normal procedure.
If a trial volunteer cannot attend a trial site, the delivery of investigational medicinal product to a patient's home is acceptable and no substantial amendment notification to the MHRA is required.
MHRA encourages sponsors to undertake a risk-assessment and record this internally.
Participants must consent verbally (and this should be documented in their notes) to providing contact details for shipping purposes. If the participant does not want to sign for the delivery due to self-isolation, then a follow up phone call could be used to confirm they have received the package. The sponsor should also consider if any training is required for administration of the investigational medicinal product.
Consideration should be given to ensuring the medicine is stored properly especially for those medicines that are susceptible to degradation. In those instances, the product integrity should be properly monitored.
During the pandemic, the MHRA supports remote monitoring when appropriate but the following points should be considered:
- Direct access to patients' electronic health records away from the site creates issues surrounding confidentiality. It is also necessary to consider the risk of accessing records in an open plan office, public space, or other locations where unauthorised persons could view sensitive information.
- Trial subjects should consent to any identifiers leaving the site and be assured that their confidentiality will be protected.
- Because of the increased pressures on clinical staff during the pandemic, extra burdens regarding the scanning and uploading of documents must not must be placed on investigators.
- The use of alternative means of oversight such as teleconferences, videoconferences is also encouraged.
During the containment phase of the broader risk mitigation strategy, the MHRA indicates that in-persons visits should be replaced by phone calls and this will not constitute a serious breach of the protocol. A substantial amendment to update the protocol will not be required. But the MHRA would expect that any protocol deviations are well documented internally.
Whilst Commission Communication in CT-1 guidance normally regards a reduction in a number of monitoring visits as a substantial amendment, if participant monitoring visits need to be reduced during the pandemic, this will not require a substantial amendment. However, the MHRA expects proper documentation on the risk assessment and rationale for the reduction in the number of monitoring visits.
Trial subject safety remains paramount. There is no general change in safety reporting requirements especially reporting of serious adverse events and submission of annual safety reports. However, the MHRA recognises that capacity issues related to COVID-19 may prevent timely reporting. Should a delay arise, the appropriate report should be made after the capacity issue is resolved.
Both MHRA and the Health Research Authority have issued blogs to provide regular updates on the guidance as the situation continues to evolve in the UK.
The content of this article is intended to provide a general guide to the subject matter. Specialist advice should be sought about your specific circumstances.