The conduct of existing clinical trials is severely affected by the pandemic. Clinical staff resource is naturally being redirected towards tackling the crisis. Travel of trial participants to and from clinical trials sites is curtailed in many countries. Even where travel is permitted, individuals may be reluctant to attend a clinical setting due to possible exposure to infected patients. Remote monitoring may be necessary, where this is a feasible option. Wet ink signatures are more difficult to obtain, and it may become necessary to post trial medicines directly to participants.
Delays to the completion of clinical trials are leading to knock-on delays in drug development programmes. A business’s pipeline may be put back by several months meaning that planned funding resources may be insufficient, and making it more difficult for businesses to engage in new fund-raising activity.
In the face of these difficulties, it will be welcome news that regulators are showing flexibility. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued guidance indicating that a flexible and pragmatic approach is being taken, provided that the safety of participants remains paramount. It may be appropriate, for example, to consider a temporary halt to a trial. Where risk assessment indicates that it is preferable to continue the trial risk mitigation steps can be used to maintain appropriate levels of safety.
Likewise, the European Medicines Agency (EMA) has issued guidance on how to manage clinical trials during the crisis. Developed alongside member state representatives, the guidance encourages consideration of measures that could be appropriate. In extreme circumstances, a temporary halt of the trial at all sites may be necessary, but other methods such as phone or video visits, and local laboratory, imaging or diagnostic testing may provide appropriate alternatives. At all times, good communication with the relevant ethics committees and regulators should be maintained, and of course, participant safety remains paramount.
US FDA guidance addresses similar issues to assist clinical trial sponsors in navigating through the current difficulties.
Clearly, sponsors and others involved in the conduct of clinical trials need to assess existing contracts to understand how delays in programmes can be managed within existing contracts, or whether contracts need to be varied. Consideration also needs to be given as to whether existing contracts may be terminated (eg for force majeure or other reasons) and how this impacts clinical development programmes.
Regulatory submissions and compliance
Many businesses are finding that regulators are very stretched. This means that approvals of new products are facing delays. Although a focus on managing the crisis and fast-tracking the review of COVID-19 related drug and vaccine candidates is necessary, this leaves other drug candidates with longer development times than expected, impacting on pipelines and investment cycles. Many contracts (eg IP licences) may be dependent on regulatory approvals being applied for or obtained by particular dates with rights to terminate or re-negotiate flowing from delays in the regulatory approval process.
Normal compliance activity is also affected, and regulators are looking at ways to introduce temporary measures in response. The MHRA, for example, is implementing a set of temporary regulatory flexibilities to respond to the crisis. A new approach to remote working by Qualified Persons will allow batch certification by an offsite QP.
During the crisis, on-site MHRA GxP inspections will be limited to the Government’s COVID-19 response or a potential serious public health risk, and assuming that remote assessment is not possible. In other situations, approaches such as office-based assessment of information and documents, with follow up using teleconferences and email. Future on-site visits may be arranged for a time when travel restrictions are alleviated.
Those in the medical devices industry will have been gearing up for the introduction of the EU’s new regulatory regime. Due to have been fully rolled out on 26 May 2020 (for general medical devices), this deadline is being pushed back by 12 months to avoid imposing unnecessary burdens on industry and regulators during the crisis. The EU Commission’s stated intention is to avoid “any potential market disruptions regarding the availability of safe and essential medical devices”. Amending legislation has been rushed through and will see the existing law maintained for the coming year.
While the delay makes sense in terms of removing any unnecessary burdens on both users of the system and member state authorities during the current crisis, many device producers will already have taken steps to adhere to the new system and may therefore not realise much benefit.
Supply chains, and moving goods and materials cross border
The life sciences sector is highly international, with multinational operations and supply chains the norm. In situations where a key supplier is unable to maintain supplies, it may be possible to find an alternative source. However, the customer will need to be aware of possible difficulties in simply switching to an alternative supplier. For example, the product or components being sourced may require access to proprietary technology. Where IP rights owned by the usual supplier that will be needed for the secondary supply, it may be necessary to seek a licence or find an alternative approach. Using an alternative supplier could lead to IP infringement or other proceedings if the necessary permissions are not in place.
Moving medicines and highly specialised materials cross border now face new restrictions, and these are subject to regular additions and updates to reflect changing national priorities. In the UK, the list of restricted medicines for parallel export has been extended to include numerous commonly used medications, like treatments for asthma, antibiotics and pain management drugs.
In the EU, a new programme to address shortages of critical medicines (the i-SPOC, or industry single point of contact) will coordinate information on anticipated or current shortages of critical medicines in order to minimise the impact of shortages.
Emergency legislation issued by the EU Commission on 15 March placed controls on the export of personal protective equipment, such as visors, mouth-nose protection and protective clothing. Permission was required for exports of certain items out of the EU. The measures are temporary and subject to regular review. Following the initial six-week period, the measures were adjusted to reduce the list of protected products.
While in some areas tighter restrictions are being imposed, others are seeing a temporary relaxation. EU rules on customs duties and VAT are being loosened in the short term to support efforts to secure vital supplies. The UK and EU countries have temporary permission to waive duties and VAT on imported supplies of much-needed medical equipment.
There is a particular focus on what digital health tools can offer during this period. Vast pools of data must be gathered in order to accurately track and predict the course of the pandemic. Current (albeit time limited) guidance on information governance indicates flexibility in approach to permit data sharing where necessary to tackle the public health crisis.
Two other areas are attracting attention.
First, remote consultations are becoming increasingly important. For primary care clinicians, telehealth previously offered convenience and flexibility. Now it may be vital for patents unable to travel, and to prevent infection of healthcare staff. UK digital health organisation NHSX is accelerating rollout of remote consultation tools.
Second, new digital apps are being developed and rolled out to gather information about the spread of symptoms among populations, and importantly to notify contacts of a possible infected person at an early stage. NHSX has begun trialing its contact tracing app on the Isle of Wight.
As always with digital health tools, compliance with patient confidentiality, and data privacy and security law, is key. NHSX emphasises the anonymous nature of the information collected by the contact tracing app, although some still have serious concerns about a project that looks like state surveillance of individuals.
Looking beyond the crisis
In the current phase of increasing or peaking infection rates, organisations are focusing on how to manage the current crisis. However, it remains important to plan for the future. Once supply chain disruption begins to lift, for example, there is likely to be competition for access to biological materials, IP and other scarce resources. Suppliers/providers may find themselves having to prioritise competing demands from customers and others. Both China and India are important global players in the supply of base materials, and manufacture in both countries is being severely affected by the crisis.
Alterations to clinical trial methodology should include plans to resume normal activity once conditions permit. Likewise, approval processes will need to be progressed as quickly as possible when the pressure on regulators begins to ease.
We are seeing the most forward thinking businesses look to the post-crisis phase, and prepare to restart or accelerate activities as restrictions begin to lift.