Regulatory responses to the global pandemic: what next for life sciences companies?
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Laura Orlando
Herbert Smith Freehills, Milan
Martina Maffei
Herbert Smith Freehills, Milan
Frederic Chevallier
Herbert Smith Freehills, Paris
Lourdes Fraguas
Herbert Smith Freehills, Madrid
Ina vom Feld
Herbert Smith Freehills, Dusseldorf
Jonathan Turnbull
Herbert Smith Freehills, London
Priyanka Madan
Herbert Smith Freehills, London
Since 11 March 2020, when the World Health Organization (WHO) declared Covid-19 a global pandemic, many countries have enacted emergency legislation, aimed at protecting their citizens’ health and guaranteeing adequate supplies of medical equipment for treatment, while maintaining business continuity to the extent possible.
Life sciences companies have responded by dedicating attention and resources to addressing the global public health emergency. At the same time, R&D and other operations have been severely affected, and increased uncertainty has its own cost: identifying risks to business continuity, product pipeline and clinical trial programmes beyond the short term is critical at this time. With a raft of emergency measures taken across Europe, it is important to identify a route through these measures to the ‘new normal’ for drug development and approval.
Our European life sciences regulatory team presents an overview of some of the key measures so far adopted, both at EU level, and nationally in the key markets of France, Germany, Italy, Spain and the UK. We then set out some of the questions which companies must consider in order to adapt and thrive in this ‘new normal’.
Clinical trials and special procedures for the approval of new medicinal products
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EMA
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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The European Medicines Agency has published Guidance on the management of clinical trials during Covid-19 pandemic (Version 3.0) EMA. The Guidance is available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf.
The EMA has also opened a specific contact email address (2019-ncov@ema.europa.eu) for developers of potential medicinal products or vaccines for Covid-19.
For products under development, in early stages and/or before the submission of MA application, EMA mechanisms include rapid scientific advice and the rapid agreement of paediatric investigation plans.
Under rapid scientific advice, the fees for scientific advice are waived and the procedure reduced to a maximum of 20 days (compared to the usual 40-70 days). Rapid agreement of paediatric investigation plans (PIPs) and compliance checks reduces total review time for a PIP for Covid-19 products to 20 days, (compared to up to 120 days active review time).
The EMA has announced the need for large, multinational trial protocols, which are most likely to be able to generate the conclusive evidence needed for the rapid development and approval of potential Covid-19 treatments.
The EMA has also announced the need for large, multinational trial protocols, which are most likely to be able to generate the conclusive evidence needed for the rapid development and approval of potential Covid-19 treatments. The Agency has
The EMA has published a note with information about all on-going clinical trials in EU for Covid-19. This is available at https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/treatments-vaccines-covid-19.
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The EMA proposes changes to on-going trials to prioritise safety and wellbeing of participants, including:
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replacing physical visits with telephone and video visits;
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extending the duration of trials;
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transferring participants away from high risk zones; and
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postponing new clinical trials.
Changes should be proportional, particularly taking into account the legitimate interest of trial sites to avoid increased time and staffing burdens.
In addition, the EMA has recently published a business continuity plan together with European Medicines Regulatory Network (EMRN). This is to avoid delays to non-Covid-19 related procedures both in terms of evaluation, maintenance and monitoring tasks to aim to fulfil normal regulatory tasks. The continuity plan is available at https://www.ema.europa.eu/en/documents/other/european-medicines-regulatory-network-covid-19-business-continuity-plan_en.pdf.
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Sponsors are to perform a risk assessment of each individual’s ongoing trial, prioritising participant safety and data validity, which should always prevail.
Sponsors should reassess risk as the situation develops.
Clinical trials for the treatment/prevention of Covid-19 will be prioritised.
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The EMA’s guidance on managing clinical trials during the Covid-19 pandemic proposes the following changes to informed consent:
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If written consent is not possible, consent may be given orally in the presence of an impartial witness.
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If potential trial patients are incapacitated, consent shall be given by a legal representative.
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In the event of life-threatening situations where it is not possible to obtain prior informed consent, informed consent will need to be acquired later, when this is allowed by national legislation.
In all cases, relevant records should be archived in the investigator's site master file.
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UK
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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Guidance has been produced by the Health Research Authority (HRA) at https://www.hra.nhs.uk/covid-19-research/, and the Medicines and Healthcare products Regulation Authority (MHRA) at https://www.gov.uk/guidance/clinical-trials-applications-for-coronavirus-covid-19.
HRA
Studies are assessed by HRA’s Director of the Approvals Service or their delegate to determine acceptance for fast-track review. New studies or amendments to existing studies will be accepted for fast-track review if they fall into various categories listed by the HRA at https://www.hra.nhs.uk/covid-19-research/fast-track-review-guidance-covid-19-studies/, and will produce interim or final published results within one year.
Applications may be reviewed as soon as within 24 hours if identified as an urgent public health study or have been determined to be studies of national interest by a government department (including in devolved administrations) or by Public Health England or equivalent national bodies.
A fast-track transparency process, in which information about each approved Covid-19 study is published on the HRA website at https://www.hra.nhs.uk/covid-19-research/approved-covid-19-research/ after approval has also been introduced.
MHRA
The MHRA is prioritising Covid-19 assessments and has put procedures in place for rapid scientific advice, reviews and approvals.
A statement from the MHRA reads:
‘We have dedicated resources to ensure this happens, as we did during the Ebola crisis when we authorised clinical trial applications within a week.’
An expedited review process is available for clinical trials relating to Covid-19 where there are public health grounds for rapid review, see guidance for applying at https://www.hra.nhs.uk/covid-19-research/fast-track-review-guidance-covid-19-studies/. This process can be as short as seven days, which was how long it took the MHRA to approve the Covid-19 Oxford Vaccine Trial request.
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MHRA guidance available at https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19 has been published for those involved with ongoing studies, wishing to restart trials, or wishing to start new studies.
The HRA has published guidance available at https://www.hra.nhs.uk/covid-19-research/covid-19-guidance-sponsors-sites-and-researchers/#newstudies for sponsors, sites and researchers who need to make changes to an existing study to manage the impact of Covid-19. The arrangements described are designed to ensure that amendments can be made quickly while subject to the appropriate oversight to protect the interests of participants.
On 21 May 2020, the National Institute for Health Research (NIHR) set out a framework to guide the restarting of NIHR research activities which had been paused due to Covid-19. The framework is available at https://www.nihr.ac.uk/news/supporting-the-restart-of-paused-nihr-research-activities/24890.
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The MHRA and HRA guidance referenced provides for special measures in relation to remote monitoring, site monitoring or administrative arrangements to reduce burden or physical contact with sites etc.
No special measures enacted relate to safety reporting. Sponsors and investigators are encouraged to consider practical steps to avoid or minimise exposure.
There has been no relaxation in relation to the timely reporting of serious adverse events (SAEs) from investigators to sponsors, or of suspected unexpected serious adverse reactions (SUSARs) from sponsors to the relevant authority.
The MHRA expects regulatory timelines for reporting to continue to be met. Sponsors who plan to introduce changes to safety recording and reporting procedures are invited to contact the MHRA.
Provision of annual list of suspected serious adverse reactions and safety report (DSUR) is expected as soon as practicable after the end of the reporting year, as per current legislation.
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For use of confidential patient data without consent, temporary arrangements are in place to support researchers doing so for Covid-19 studies. These arrangements replace the Confidentiality Advisory Group (CAG) review, although the CAG is providing advice as part of the fast-track process. More information about the use of patient data is available at https://www.hra.nhs.uk/covid-19-research/guidance-using-patient-data/.
Provisions for seeking emergency consent are published at https://www.hra.nhs.uk/covid-19-research/seeking-consent-covid-19-research/.
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France
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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The French Health Agency (ANSM) has implemented an accelerated initial assessment of clinical trials authorisations ANSM, the General Management of Health and the Committee for the Protection of Persons. An average seven days have been necessary to authorise a clinical trial, compared to 60 days in normal times. ANSM has disclosed that it has authorised about 66 per cent of the 52 clinical trial projects. See https://ansm.sante.fr/S-informer/Points-d-information-Points-d-information/Essais-cliniques-dans-la-prise-en-charge-des-patients-atteints-du-COVID-19-point-d-etape-sur-les-projets-autorises-par-l-ANSM-Point-d-Information.
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New and ongoing trials are allowed to proceed, but measures have been implemented to allow: (1) staying inclusions due to Covid-19; (2) resuming such inclusions; (3) visiting patients remotely for follow-ups; (4) dispensing the experimental treatments for longer periods than planned in the protocol; (5) delivering the experimental treatments to the patient’s home; (6) monitoring trials; and (7) dealing with vigilance and infection during clinical trials. See https://www.ansm.sante.fr/Activites/Essais-cliniques/COVID-19-Essais-cliniques-en-cours/(offset)/0
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See the left hand column.
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There have been no specific developments but the ANSM has noted that most Covid-19 related clinical trials involve hospitalised patients.
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Germany
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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The National Infection Protection Act has been adapted, with new regulations added. The Federal Ministry of Health (BMG) can issue exemptions from the provisions of the German Medicines Act (AMG) and other legal regulations. The SARS-CoV-2 Drug Supply Regulation has been issued. The procedure for clinical trials on the off-label use of drugs for treatment of Covid-19 diseases has been accelerated by reducing the objection period of the Federal Joint Committee from eight weeks to five working days.
The BMG has declared a lack of approved drugs for Covid-19 treatment, enabling federal state authorities to allow a temporary exemption from AMG requirements in individual cases, for example, temporarily to place non-authorised medicinal products on the market.
Applications and requests for advice in direct connection with clinical trials and drug development related to Covid-19 are prioritised.
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Clinical trials are not suspended in general, although some have been voluntarily paused.
Sponsors are asked to evaluate whether continuation of patient recruitment is reasonable or should be discontinued. If it is necessary to discontinue recruitment, the Federal Institute for Drugs and Medical Devices must be notified. To simplify matters, the Federal Institute does not insist on the submission of an amendment form. A resumption of recruitment requires a new variation notification, subject to approval from the responsible higher federal authority and the relevant ethics committee.
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Provisions related to safety reporting in clinical trials (sections 12 and 13 GCP-V) continue to apply. These relate to the reporting of serious adverse events (SAE), that has to be reported immediately by the investigator to the sponsor, unless the licensed trial protocol provides otherwise, as well as the sponsor's reporting obligations towards federal higher authorities, other authorities, and ethics committees.
If, in connection with an SAE report, a trial participant is unable to visit the trial centre in person, initial communication with the investigator can take place by telephone. In
such cases, a decision must be made as to whether the participant’s appearance in person, eg, for further testing, is necessary based on safety considerations.
If it is intended to replace regular visits in part or completely to telephone contact or telemedical visits. This is to be submitted to the relevant federal higher authority and appropriate ethics committee as a notification of variation subject to approval. In case of notifications of variation that affect safety reporting, the sponsor is requested to include a risk analysis of the effects of these changes on the safety of trial participants and the validity of the data collected.
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Reference is made to the Guidance on the management of clinical trials during Covid-19 pandemic (Version 3.0) of the EMA, which also includes changes on informed consent. The Guidance is available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf.
Accordingly, all trials need to remain in compliance with the national legal framework. For trials involving Covid-19 patients, alternative procedures are possible if a written consent is not feasible, eg, orally given consent by the trial participant (article 2(j) of Directive 2001/20/EC) in the presence of an impartial witness.
There may be a need to re-consent already included trial participants, but visits to trial sites for the sole purpose of obtaining re-consent should be avoided.
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Italy
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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Clinical trials are covered by Italian Decree Law of 17 March 2020 no 18 (DL 18/2020) and specific guidance issued by the Italian Medicines Agency (AIFA).
The AIFA has implemented simplified procedures for Covid-19 clinical trials and a more responsive procedure for authorising the off-label use (and reimbursement) of pre-approved medicinal products.
Pursuant to article 17 of DL 18/2020, new clinical trials are:
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There is no general suspension, but measures are in place to protect the health of the patients enrolled and to avoid possible infections.
For example, if the site is closed for containment measures and the continuity of the study cannot be maintained, the study must be halted temporarily or transferred to the closest (already authorised) active trial site.
Recruitment and the inclusion of new patients should be avoided as much as possible, with exception, eg, in the absence of a valid therapeutic alternative. In the event of suspension by the sponsor, it is necessary to notify a substantial amendment to the ethics committee of all the centres involved.
New trials have not been prohibited, although Covid-19-related trials are prioritised.
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As there is no specific exemption, all the provisions relating to safety reporting apply.
According to the indications contained in the Presidential Decrees (DPCM) and in guidance adopted at a regional level, sponsors and CROs are invited to set up a risk-based action plan, to protect trial participants, minimise contact between participants, investigators and other staff, and avoid overload of healthcare facilities.
The carrying out of procedures at the participant’s home, carried out by the staff from the trial centre or by third parties, may be considered.
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Standard methods are preferred, however alternative procedures are possible, eg, the recording of telephone consent or via photographs of documentation.
Consent must be given as soon as possible; it is in any case necessary to obtain written consent.
The general rules related to processing of personal data remain in force.
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Spain
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Special provisions for clinical trials relating to Covid-19 vaccines or treatment
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New and ongoing clinical trials not relating to Covid-19
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Risk assessment and communication with authorities
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Informed consent for new studies
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Measures to speed up and promote clinical trials and observational studies on Covid-19 were published by the Spanish Medicines Agency (AEMPS) on 5 May 2020 (11/2020). These are available at
https://www.aemps.gob.es/informa/notasinformativas/medicamentosusohumano-3/2020-medicamentosusohumano-3/actuaciones-de-la-aemps-para-agilizar-y-fomentar-los-ensayos-clinicos-y-estudios-observacionales-sobre-covid-19/.
Applications are evaluated and assessed within a maximum of 15 days.
Sponsors or researchers who have a clinical trial project of this type should send their application to the AEMPS through the clinical trials portal, informing them of their application by sending a message to aecaem@aemps.es with the subject ‘URGENT COVID-19’, and identifying the trial with the EudraCT number. The title of the trial should include the word Covid-19.
To facilitate implementation, fee exemptions and simplification of contracts between sponsor and centre are recommended.
The Spanish Data Protection Office has authorised remote monitoring with a commitment to confidentiality and a security protocol for remote connection.
The AEMPS encourages the rapid analysis and submission of the results of the clinical trials. The Agency also states these trials are a priority and all efforts are aimed at sharing information and outcomes.
In this regard, the AEMPS has published a press release on 22 May 2020 with a link to all ongoing trials for Covid-19. The press release is available at https://www.aemps.gob.es/la-aemps/ultima-informacion-de-la-aemps-acerca-del-covid%E2%80%9119/informacion-sobre-investigacion-clinica-sobre-la-covid-19/.
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Exceptional measures relating to Covid-19 clinical trials were published by the AEMPS on 16 March 2020 (4/2020). These are available at https://www.aemps.gob.es/informa/notasinformativas/medicamentosusohumano-3/2020-medicamentosusohumano-3/medidas-excepcionales-aplicables-a-los-ensayos-clinicos-para-gestionar-los-problemas-derivados-de-la-emergencia-por-covid-19/. The measures aim at safeguarding as far as possible, the trial, the safety and welfare of patients and the reliability of trial results. They make recommendations on the scheduled in-person testing of patients, patient access to trial medication, scheduled monitoring, and the transfer of patients between clinics.
The relevant body of the autonomous region may set out appropriate measures to ensure that medicinal products needing clinical trials are dispensed without the trials having to be carried out on hospital premises.
It may also establish measures to ensure patients participating in a trial receive their medication at home, as well as measures to administer, on an exceptional basis, medication for hospital use outside of the hospital facility whenever the conditions of the patient, the disease, the medication and the epidemiological situation so advise.
The above measures may be adopted without authorisation from AEMPS or from research ethics committees. However, any change to the clinical trial protocols must be reported within four months of the end of the Covid-19 crisis, ie, at the end of the state of emergency – 7 June, (subject to extensions).
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The is no specific exemption, all risk assessment provisions apply.
The sponsor shall perform a risk assessment on each individual ongoing trial, prioritising trial participant safety and data validity, which should always prevail.
The sponsor should reassess risk as the situation develops.
Clinical trials for the treatment or prevention of Covid-19 will be prioritised.
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The Spanish Pharmaceutical Industry Code of Conduct on the protection of personal data in clinical trials states, in accordance with GDPR, that once consent to take part in a clinical trial has been given, personal data processing for scientific research is lawful based on the legitimate interest pursued by the researcher. This is subject to appropriate safeguards. Therefore, further processing in compatible activities (ie, new studies) is also lawful.
Please note that EMA Guidance on management of clinical trials should be also applied.
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Centralised marketing authorisations
On 4 May 2020, the European Medicines Agency (EMA) published a press release on how the Agency is fast-tracking the development of medicines and vaccines relating to Covid-19. Two main measures have been adopted.
A rolling review allows the EMA to assess data for a promising medicine on a rolling basis as it becomes available. The usual procedure entails submitting all data supporting the marketing authorisation application at the start of the evaluation procedure. The rolling review permits the EMA to review data as it becomes available, as CHMP rapporteurs are appointed while development is in progress. Once the data package is considered complete, the sponsor submits a formal application for marketing authorisation to the EMA, which is then processed within a shorter time span.
An accelerated assessment procedure can reduce the length of review for products of major public health interest from 210 days to less than 150 days. In practice, evaluation periods will be reduced to the absolute minimum where there is an urgent public health need.
The EMA may also provide support in cases of compassionate use programmes. Such programmes are set up at the level of individual EU Member States, to give patients access to treatments still under development and that have not yet received a marketing authorisation.
What’s next
The Covid-19 pandemic does present the pharmaceutical sector with an opportunity to capitalise on rapid research and product development, taking advantage of the temporary changes in regulatory rules governing the approval and supply of new products. The development and availability of treatments and vaccines for EU patients, including those with Covid-19, remains the priority for the European medicines regulatory network (EMRN) led by EMA, in close collaboration with Member States’ regulatory authorities and the European Commission. In this unprecedented global challenge, it has been vital that the EU regulatory system continues to address all patients’ needs.
Given the developing situation, the extent of the long-term impact on the pharmaceutical sector is difficult to estimate, but we can assume any delays in application submissions will result in a later accumulation of submissions. The agreement reached within the EMRN as to the principles for the handling of regulatory procedures in a business continuity context due to Covid-19, has resulted in some changes that, if prove efficient, may be retained. For example, much effort and resources from EMA, member states regulatory authorities and the EC has been put into fulfilling usual regulatory tasks regarding evaluation, maintenance and monitoring. In the short term, for non-Covid-19-related products, companies should think about their current approach to working with regulators, and as and when interim measures expire, and maintain a proactive, pragmatic dialogue with regulators.
The attempt at continuing work as usual wherever possible has been remarkable, and this will in itself, bring new opportunities and challenges for pharmaceutical companies and for the EU regulatory system. The extent of the long-term impact on the regulation of the sector is difficult to estimate, but life sciences companies will need to consider that:
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given the resources awarded to Covid-19 related research, regulators will take into account the need to be prepared for similar pandemics in future, and therefore establish SOPs incorporating best practices applied in recent months, and assessing lessons learnt;
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companies will need to adapt their procedures to the regulatory changes which may come into force, particularly if timelines become more flexible, always within a constructive dialogue with regulators; and
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some changes may become long-term or permanent, a trend that looks set to accelerate is towards decentralised trials, as such the adoption of new technologies, and a renewed focus on data privacy seems inevitable.
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