The Learning Portal will be under maintenance Saturday, 8 August between 6 AM and 6 PM EST. Portal functionality will be unavailable during this window.
We apologize for any inconvenience caused during this time.

RAPS is closely monitoring developments in the Coronavirus (COVID-19) outbreak. See our public safety page for the latest updates.

 
Regulatory Focus™ > News Articles > 2020 > 7 > Managing uncertainty: Regulatory reporting in multinational trials during COVID-19

Managing uncertainty: Regulatory reporting in multinational trials during COVID-19

Posted 13 July 2020 | By Ioana Ionita, MA 

Managing uncertainty: Regulatory reporting in multinational trials during COVID-19

This article discusses regulatory reporting challenges for multinational clinical trials during the COVID-19 pandemic. The author covers the pandemic’s impact on clinical research, national guidelines, and harmonization, as well as the challenge of assessing what is reportable and how to submit COVID-19 risk mitigation measures. She offers real-world experience on how she and her colleagues stopped and restarted recruitment in ongoing multinational clinical trials, and how those actions were reported globally. She concludes that close collaboration between sponsors, CROs, local affiliates, investigational sites, and health authorities is important in choosing strategies under challenging circumstances and when no precedent applies.
 
Introduction
Disruption is currently the central theme globally as communities and industries deal head-on with the COVID-19 pandemic. What was initially deemed a localized health challenge has become an unprecedented health crisis in a superconnected, globalized world. All industries have been affected by the pandemic, but pharmaceutical companies have found themselves center stage in this rapidly evolving crisis. The industry has come under increasing pressure to deliver safe, effective therapies and vaccines as quickly as possible, yet are faced with limited resources and inadequate guidance. Those who are managing ongoing and new clinical trials – already a challenge in non-pandemic circumstances – have had to navigate unknown territory to find a reasonable path forward while mitigating risks. Given that context, this article will focus on the regulatory reporting challenges for those conducting multinational clinical trials during the COVID-19 pandemic.
 
Impact of the pandemic on clinical research
It is too early to assess the pandemic’s impact on clinical research fully, but a look at the numbers offers some insight. It is estimated that more than 2,850 clinical trials were being conducted during April 2020 in regions that became affected by COVID-19 restrictions, which included complete lockdown or more limited measures. About 900,000 patients were participating in clinical trials that faced an uncertain future as the crisis unfolded.1 Sponsors were forced to weigh the risks associated with continuing the clinical activities against the expected benefits for the patients, and they had to do so quickly. In addition, the validity of the data already collected in these ongoing clinical trials had to be a deciding factor in how they proceeded.
 
When identifying the most appropriate measures for a multinational clinical trial, it is crucial to ensure measures are applicable globally. Doing so becomes more difficult in a crisis because the regulatory landscape becomes more fluid as daily realities around the crisis keep shifting. Designing a structured approach for managing a clinical trial under those circumstances requires close collaboration among sponsors, clinical research organizations (CROs), trial site representatives, and health authorities. The most common measures and steps to be considered would likely include:
 
  • Halting enrolment in active clinical trials and postponing the start of new trials.2
  • Shipping the investigational medicinal product to patients’ homes.3
  • Minimizing physical visits to trial sites by having phone or video check-ins, where possible.4
  • Transferring trial participants to other investigational sites, if needed.5
  • Using local laboratory or relevant clinical facilities authorized/certified for routine or critical laboratory tests, imaging, or other diagnostic tests.6
  • Using remote access to source data for monitoring purposes only in justified, exceptional cases, and only when necessary.7
 
These options would have comprised the standard assessment for a clinical trial regulatory leader managing global submissions before the pandemic because the rules were in place and would not change during the assessment. During a pandemic, however, guidelines must be drafted and revised in real time.
 
National guidelines and harmonization challenges
The International Conference on Harmonization’s good clinical practice guidelines, clinical trial legislation, and information on previous clinical trial practices were not adequate for guiding sponsors, CROs, and trial site representatives in the context of the COVID-19 pandemic.8-10 Solutions that originally seemed viable, as detailed above, were not in line with the standard approach from a regulatory perspective in the pandemic environment. The questions for each decision taken during this time had to consider the critical aspects presented in the figure below.

 Ionita_Figure_final-(1).png

Real-world experience: Regulatory reporting on halting and restarting recruitment
Halting recruitment for ongoing trials, or postponing the start of new trials, are among the most common risk mitigation decisions sponsors take. Some findings have suggested more than 50% of companies have stopped recruitment for trials during the pandemic, and 75% have postponed the start of new trials.1 Below is an analysis of how these risk mitigation measures can be reported to regulatory authorities. The information is based on the author’s real-world experience in managing multiple multinational clinical trials as a regulatory lead during the pandemic. Because halting recruitment will be followed by restarting recruitment after the pandemic has subsided, the analysis also addresses regulatory reporting of restarting.
 
The above figure outlines the questions the regulatory professional must address in the context of COVID-19 minimizing measures. The author and colleagues used the decision tree to decide the regulatory approaches in halting recruitment and determining the challenges and key principles that guide the pharmaceutical companies in conducting clinical trials during this period.
 
Question A: Is halting recruitment in line with regulatory requirements across all active countries in the specific clinical trial?
If the response to this first question was an unequivocal Yes, it meant the measure could be applied across all regions affected by the pandemic. Similarly, the same response would be applicable for the restart of recruitment activities once the epidemiologic context becomes favorable, and healthcare systems return to normal operations.
 
On the other hand, if the sponsors were to swap recruitment halt with another measure, such as remote source data verification (SDV), a response of No would be correct. Harmonization between national guidelines on remote SDV has not been reached. Consequently, although some measures can be applied across centers in different countries, others can be used only at the local level, based on specific national requirements.
 
Question B: If the response to Question A is Yes, then how should halting recruitment and restarting be reported and implemented in each country in line with national guidelines?
When sponsors decide at the global level to halt recruitment in ongoing clinical trials, the regulatory leader faces the demanding task of drafting the reporting strategy for this measure based on study-level factors and national guidelines.
 
In non-pandemic circumstances, recruitment is stopped because of a potential change in benefit-risk balance (that is, a safety-related issue), or because of difficulties in reaching potential subjects for participation in the clinical trial, as noted in Clinical Trials Regulation (EU)NO 536/2014.11 Neither of those categories can be used in the context of the pandemic.
 
In March 2020, health authorities in Europe began drafting and releasing guidelines for clinical trials during the pandemic to help the healthcare community adapt to the shifting context in as consistent a manner as possible.12-14 However, identifying what is reportable and what the expected reporting strategy would be for each country was not an easy task, as the five potential scenarios outlined in the above figure suggest.
 
In our experience, some guidelines explicitly mentioned that a notification was not expected if recruitment was halted because of the COVID-19 pandemic rather than for safety-related reasons (e.g., UK,4 Chile15). However, a significant number of authorities in the trials we managed did not mention any approach (e.g., Austria16 and Slovenia and Guatemala [based on direct communication with health authorities in the latter two countries]). In those circumstances, sponsors and regulatory leads were forced to choose ad hoc strategies in the absence of relevant information. Balancing overreporting with regulatory compliance was difficult in this context, and regulatory professionals generally chose to notify authorities of this measure.17
 
Going forward with the review of the requirements for halting recruitment, we noticed a significant number of authorities expected to be informed of this type of measure, but the method of reporting was not suggested in the guidelines (e.g., Czech Republic2). Despite those omissions by some countries, other countries did recommend approaches, including:
 
  • Notifications (e.g., Bosnia Herzegovina,18 Colombia,19 Croatia,20 South Africa and India [based on direct communication with health authorities in the latter two countries])
  • Halt of recruitment to be documented in a summary of all actions taken during the COVID-19 pandemic (e.g., Spain6) or in the next annual safety report (e.g., Brazil21)
  • Substantial amendments (e.g., Estonia,22 Finland23)
  • Substantial amendments for information only (e.g., France,3 Italy24)
 
That list is not exhaustive, but the degree of variation demonstrates the challenges regulatory leads face. It is worth mentioning that some of the above requirements were published post factum after sponsors had already decided to suspend the inclusion of new trial subjects and reported the measure based on ad hoc decisions and interpretation of available information.
 
In the event of restarting recruitment activities, sponsors must consider a new variable – the timing for resumption of enrolment. Again, there is no harmonization among countries on whether prior approval for resumption is needed or how soon after submission of the restart notification a trial may begin. There are multiple approaches, however, depending on which country the trial site is in. For example:
 
  • Notifications are not needed (e.g., UK,4 US,5 Spain6), mostly countries in which halting recruitment because of the COVID-19 pandemic did not have to be reported at all or could be reported later in summary reports.
  • Notifications or amendments for information only where no approval is expected (e.g., Belgium,25 France3).
  • Substantial amendments that require approval before implementation (e.g., Germany7).
 
In addition to the above examples, when trial enrolment is restarted some authorities expect submission of risk assessments demonstrating that decision to restart is based on thorough consideration of the impact, both on patient safety and data integrity. Again, regulatory experts find themselves in the critical and uncomfortable position of providing solutions in times of uncertainty, when not all authorities have provided expectations regarding the resumption of enrolling submissions.
 
Conclusion
The COVID-19 pandemic has been a decisive point in clinical trials regulatory affairs. It has highlighted the complexity of managing multinational clinical trials that must meet changing national guidelines while maintaining patient safety and the scientific value of the research during a global crisis. The lesson learned is that a close collaboration between sponsors, CROs, local affiliates, investigational sites, and health authorities is of utmost importance in choosing the correct strategy in difficult circumstances and when no precedent applies. The role of the global CROs is significant in these circumstances, because they have the most comprehensive overview of the regulations and are in regular contact with a range of regulatory agencies. Thus, CROs are in the best position to act and advise quickly and decisively.
 
References
  1. McKinsey & Co. COVID-19 implications for life sciences R&D: Recovery and the next normal. https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/covid-19-implications-for-life-sciences-r-and-d-recovery-and-the-next-normal. Published 13 May 2020. Accessed 7 July 2020.
  2. State Institute for Drug Control [Czech Republic]. Opinion of SÚKL's Department of Clinical Trials on medicinal products on ongoing clinical trials and to-be-commenced clinical trials in light of the COVID-19 epidemiological situation of 25 June 2020. http://www.sukl.eu/medicines/opinion-of-sukl-s-department-of-clinical-trials-on-medicinal-1. Last updated 1 July 2020. Accessed 7 July 2020.
  3. Agence Nationale de Securité de Médicament et des Produits de Santé [France]. Covid 19 ‒ Ongoing clinical trials. https://www.ansm.sante.fr/Activites/Essais-cliniques/COVID-19-Ongoing-clinical-trials/(offset)/1#paragraph_172505. Published 20 March 2020; last updated 20 May 2020. Accessed 7 July 2020.
  4. Ministry of Health and Regulatory Affairs [UK]. Managing clinical trials during coronavirus (COVID-19): How investigators and sponsors should manage clinical trials during COVID-19. https://www.gov.uk/guidance/managing-clinical-trials-during-coronavirus-covid-19 . Published 19 March 2020; last updated 21 May 2020. Accessed 7 July 2020.
  5. US Food and Drug Administration. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency: Guidance for industry, investigators, and institutional review boards. https://www.fda.gov/media/136238/download. Published March 2020; last updated 2 July 2020. Accessed 7 July 2020.
  6. Agencia Espanola de Medicamentos y Productos Sanitarios [Spain]. Exceptional measures applicable to clinical trials to manage problems arising from the COVID-19 emergency. https://www.aemps.gob.es/informa-en/exceptional-measures-applicable-to-clinical-trials-to-manage-problems-arising-from-the-covid-19-emergency/?lang=en. Last updated 1 July 2020. Accessed 7 July 2020.
  7. Paul-Ehrlich Institut [Germany]. Clinical trials during the COVID-19 pandemic. https://www.pei.de/EN/regulation/clinical-trials/covid-19/covid-19-node.html;jsessionid=EF8CC6462B2B1D95828041A7BC8EE810.2_cid319. Updated 26 May 2020. Accessed 7 July 2020.
  8. European Medicines Agency. ICH E6 (R2) Good clinical practice. https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice. Last updated 15 December 2016. Accessed 10 July 2020.
  9. European Medicines Agency. EudraLex ‒ Volume 10 ‒ Clinical trials guidelines. https://ec.europa.eu/health/documents/eudralex/vol-10_en. Last updated 28 April 2020. Accessed 10 July 2020.
  10. US Food and Drug Administration. Clinical Trials Guidance Documents. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-trials-guidance-documents. Last updated 21 January 2020. Accessed 10 July 2020.
  11. European Commission. Clinical Trials Regulation (EU)NO 536/2014, Draft, Questions & Answers, Version 2.3. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/regulation5362014_qa_en.pdf. Published November 2019. Accessed 7 July 2020.
  12. European Medicines Agency. Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic, Version 3. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf. Published 28 April 2020. Accessed 7 July 2020.
  13. European Medicines Agency. Guidance on how to manage clinical trials during the COVID-19 pandemic (v3, 28 April 2020). Presentation for a joint EMA, EC, CTFG/HMA webex conference. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_pres_en.pdf. Presented 15 May 2020. Accessed 7 July 2020.
  14. European Medicines Agency. Guidance for medicine developers and companies on COVID-19. https://www.ema.europa.eu/en/human-regulatory/overview/public-health-threats/coronavirus-disease-covid-19/guidance-medicine-developers-companies-covid-19#advice-for-sponsors-and-stakeholders-involved-in-clinical-trials-for-covid-19-treatments-and-vaccines-section. Last updated 1 July 2020. Accessed 7 July 2020.
  15. Institute of Public Health [Chile]. Information on medication in clinical trials during the global COVID-19 pandemic [in Spanish]. http://www.ispch.cl/sites/default/files/Informativo%20Entrega%20de%20medicaci%C3%B3n%20en%20domicilio%20-%20COVID-19_pcs.pdf. Published 11 May 2020. Accessed 10 July 2020.
  16. Austrian Federal Office for Safety in Healthcare. Clinical trials and COVID-19. https://www.basg.gv.at/en/healthcare-professionals/clinical-trials/klinische-studien-und-covid-19/haeufige-fragen. Accessed 10 July 2020.
  17. Pamungkas D, Pankow R, Roder B. Parexel website. Critical considerations for restarting clinical trials in countries recovering after the COVID-19 pandemic. https://www.parexel.com/news-events-resources/blog/critical-considerations-restarting-clinical-trials-countries-recovering-after-covid-19-pandemic. Published 22 May 2020. Accessed 7 July 2020
  18. Agency for Medical Products and Medical Devices. Instructions for all sponsors and applicants for obtaining a license to conduct clinical trials during the state of emergency in Bosnia Herzegonevia [in Bosnian]. http://www.almbih.gov.ba/_doc/klinicka/COVID.pdf. Accessed 10 July 2020.
  19. National Surveillance Institute for Medicines and Foods [Colombia]. INVIMA adopts new administrative measures due to the emergency triggered by COVID-19 [in Spanish]. https://www.invima.gov.co/web/guest/invima-adopta-nuevas-medidas-administrativas-en-el-marco-de-la-emergencia-ocasionada-por-el-covid-19?redirect=%2Fweb%2Fguest%2Farticulos-de-interes-coronavirus-covid-19. Published 24 June 2020. Accessed 10 July 2020.
  20. Ministry of Health [Croatia]. Health guidelines related to conducting clinical trials during the COVID1-19 pandemic [in Croatian]. https://zdravlje.gov.hr/UserDocsImages/2020%20Sektor%20za%20lijekove%20i%20medicinske%20proizvode/MIZ_Smjernice%20za%20vrijeme%20pandemije%20bolesti%20COVID-19%20v.%202.pdf . Accessed 10 July 2020.
  21. National Agency of Health Surveillance, AANVIS [Brazil]. Technical note, No. 22 [in Spanish]. http://portal.anvisa.gov.br/documents/219201/4340788/SEI_ANVISA+-+1048433+-+Nota+T%C3%A9cnica+-+COPEC.pdf/b07930de-5899-4cb7-b435-36791547941f. Dated 15 June 2020. Accessed 7 July 2020.
  22. State Agency of Medicines [Estonia]. Guidance on clinical trial management in the context of COVID-19 pandemic. https://www.ravimiamet.ee/sites/default/files/guidance_on_clinical_trial_management_in_the_context_of_covid-19_v3_01_1.pdf. Published 1 April 2020. Accessed 7 July 2020.
  23. Finnish Medicines Agency. Clinical trials during the coronavirus epidemic (COVID-19) [in Finnish]. https://www.fimea.fi/-/kliiniset-laaketutkimukset-koronavirusepidemian-covid-19-aikana. Dated 13 March 2020. Accessed 7 July 2020.
  24. Agencia Italiana del Farmaco. Clinical trials’ management in Italy during the COVID-19 (coronavirus disease 19) emergency. https://www.aifa.gov.it/documents/20142/871583/Comunicato_gestione_studi_clinici_in_emergenza_COVID-19_EN_12.03.2020.pdf/ee1f33e3-bb3e-9ce9-2a93-b33e88eea94d. Not dated. Accessed 7 July 2020.
  25. Federal Agency for Medicines and Health [Belgium]. Addendum to the guidance on the Management of clinical trials during the COVID-19 (Coronavirus) pandemic, v2. https://www.afmps.be/sites/default/files/content/national_guidance_corona_20200429c_clean.pdf. 29 April 2020. Accessed 10 July 2020.
 
About the author
Ioana Ionita, MA, is a regulatory affairs senior associate at Parexel. She is currently completing a Post Graduate Diploma in Drug Development at King’s College London. She has more than 8 years of experience in pharmaceutical industry with a current focus on regulatory affairs in clinical trials, being responsible for regulatory strategy design, completion of regulatory deliverables and contribution to internal regulatory intelligence databases. She can be contacted at Ioana.ionita@parexel.com.
 
Citation Ionita I. Managing uncertainty: Regulatory reporting in multinational trials during COVID-19. Regulatory Focus. July 2020. Regulatory Affairs Professionals Society.
 

Regulatory Focus newsletters

All the biggest regulatory news and happenings.

Subscribe