Open access Editorial Clinical research disruption in the post-­ COVID-19 era: will the pandemic lead to change? Domenica Lorusso,1 Isabelle Ray-­Coquard,2 Ana Oaknin,3 Susana Banerjee4 To cite: Lorusso D, The unprecedented situation we are facing treatment delays and modifications on Ray-­Coquard I, Oaknin A, et al. has strongly disrupted the clinical research a case-­ by-­ case basis, taking into account Clinical research disruption in the post-­COVID-19 era: rules. Nevertheless, for the scientific commu- the characteristics of the patient and the will the pandemic lead nity, it may represent the opportunity to disease.3 In addition to routine patient care, to change? ESMO Open learn important lessons. The COVID-19 the imperative of reducing the number of 2020;5:e000924. doi:10.1136/ pandemic suggests that it is possible to alle- non-­urgent visits to the hospitals, which char- esmoopen-2020-000924 viate redundancy in clinical trials, and while acterised the last 6 months, had implications preserving the rigour of a study, can offer for research institutions performing clinical Received 18 July 2020 a new, less burdened and more inclusive trials. An Italian survey of medical oncolo- Revised 7 September 2020 vision of clinical research for the scientific gists reported that both clinical research Accepted 8 September 2020 community of tomorrow. This perspective and scientific activities were reduced in over Published online article describes clinicians’ vision of how the 80% of respondents.4 13 October 2020 pandemic could change the roles of clinical Although conversion to telemedicine research. has maintained the continuity of care for Since the beginning of the SARS-­COV2 many patients, the COVID-19 pandemic has © Author (s) (or their employer(s)) 2020. Re-­use outbreak in Wuhan, more than 24 million massively disrupted clinical research and permitted under CC BY-­NC. No people have been infected all around the many cancer centres halted clinical trial commercial re-­use. Published world and more than 800 000 have died activities including patient recruitment. by BMJ on behalf of the from the disease so far. In this scenario, Regulatory Agencies have disseminated European Society for Medical Oncology. Europe is facing one of the worst crises extraordinary measures to guide healthcare 1 Scientific Directoracte and that our National Health Systems have ever workers to continue clinical trials ensuring Gynecologic Oncology Unit, encountered in the last 50 years. Six months patient safety and maintaining data quality. Department of Women and Child after the first COVID-19 diagnosis, the lock- The implementation of these measures Health, Fondazione Policlinico down is being eased in European countries has helped mitigate the negative effects of Universitario A. Gemelli IRCCS, and our lives are slowly adapting to ‘a new the pandemic on the clinical research field Rome, Lazio, Italy 2 Medical Oncology Department, normality’. (https://​ec.​europa.​eu/​health/​sites/​health/​ Centre Leon Berard nd Providing care to immunocompromised files/​files/​eudralex/​vol10/​guid​ance​clin​ical​ University Claude Bernard, Lyon, patients with cancer during this pandemic trials_​covid19_​en.​pdf). France has been extremely challenging and oncol- Hospitals have needed to prioritise clinical 3 Department of Oncology,Institute of Oncology, ogists face many challenges in providing activities managing patients and staff suffering Vall d'Hebron University cancer care during the COVID-19 outbreak. from COVID-19. Therefore, carrying out clin- Hospital, Barcelona, Catalunya, Data from China reported that patients with ical trials according to the rigid interpretation Spain cancer who are infected with COVID-19 are of GCP-­ICH (Good clinical practices–Inter- 4 MBBS MA FRCP, The Royal at 3.5 times the risk of requiring mechan- national Conference on Harmonisation) Marsden NHS Foundation Trust nd Institute of Cancer Research, ical ventilation or intensive care unit (ICU) rules was not always practically feasible. London, UK admission, compared with the general As we adapt to ‘the new normal’, there is a population.1 Additionally, the limitation of feeling among some healthcare workers Correspondence to resources in outpatient settings, including that the important lessons learnt during the Professor Domenica Lorusso, Scientific Directoracte and administrative staff and specialists, has pandemics will disappear with the end of the Gynecologic Oncology Unit, hindered the routine care of patients.2 emergency phase. Department of Women and Child National and international cancer societies In the field of clinical research in oncology, Health, Fondazione Policlinico published priority-­ driven guidelines for for instance, we learnt that a reasonable Universitario A. Gemelli IRCCS, Rome, Italy; the management of oncohaematological balance can be achieved between maintaining ​domenica.​lorusso@​ patients on therapy during the COVID-19 the scientific integrity of the study, patient policlinicogemelli.​it pandemic and recommended considering safety and regulatory burden. During the Lorusso D, et al. ESMO Open 2020;5:e000924. doi:10.1136/esmoopen-2020-000924 1 Open access COVID-19 era, both individual researchers and research facing telemedicine and may have considerable impli- organisations have realised that there is a different way cations for the acceptance of telemedicine services.12 of delivering clinical research and that ‘flexibility’ and Moreover, the relationship between telemedicine re- ‘altruism’, which have been keywords of the COVID-19 imbursement rules and access to care is complex; al- era, may represent one of the legacies as we move forward though the COVID-19 pandemic has certainly brought within the post-­COVID-19 world. increased coverage for telemedicine services, nation- Practical solutions used during the pandemic that wide standardisation of payment policies is still lack- merit the consideration of long-­term implementation in ing.13 With the second-­largest burden of COVID-19 in clinical research include the following. the world, for instance, Italy does not currently include 1. Telemedicine: the COVID-19 pandemic led to an un- telemedicine in the essential levels of care granted to precedented change in clinical operations, motivating all citizens within the National Health Service and physicians and healthcare systems worldwide to rap- no formal input was given on telemedicine by health idly implement telemedicine programmes to reduce authorities, despite high pressure on health services or replace in-­person visits and to allow workforce sus- during the first phase of the epidemic. However, the tainability and staffing.5 Before the pandemic, tele- time has arrived to change this situation, and experts medicine was underused while actually, it is quickly from different fields should work together on this im- becoming the preferred mode of delivering care for portant issue. patients with cancer including follow-­up, on-­treatment 2. Remote monitoring visits: given the pandemic, alter- and second opinion consultations. When asked about native mechanisms of oversight and monitoring have the perception of safety to attend research visits ‘re- been implemented including remote monitoring. Lo- motely’ or in-­person, half of clinical trial participants cal data protection policies in many parts of Europe preferred phone visits6 or telehealth that is enhanced often precludes the remote source data verification by face-­to-­face communication.7 A 2015 Cochrane re- (eg, providing the sponsor with copies or remote ac- view examined the impact of telemedicine involving cess to electronic medical records). It is evident that remote monitoring compared with in-­person or tele- such a model cannot work alone, nevertheless, a mixed phone visits for chronic conditions, including diabetes (on-­site and remote), risk-­based model that takes into and heart failures, and found similar health outcomes.8 consideration national and local restrictions and the Larson et al9 showed that telemedical intervention in urgency of source data verification can be permanent- patients with cancer is comparable with face-­to-­face in- ly implemented in the new research organisational teraction meetings regarding the quality of life but no model. Remote monitoring for some clinical trials is data exist about the oncological outcome in patients feasible and cost saving for the sponsor. This may be who received telemedical advice. These measures, al- particularly relevant for academic-­sponsored trials, giv- though necessary in the context of the pandemic, serve en that on-­site monitoring can account for about 20% as an opportunity to reconsider the utility of frequent of the total trial budget.14 in-­person hospital visits for patients enrolled in clinical 3. Laboratory tests: during the pandemic, when it was trials, particularly when the therapeutic is an oral drug not feasible for patients to travel to the clinical trial that can be delivered by courier service. Moreover, less centre, it was acceptable that blood tests, imaging or than 5% of cancer clinical trials adequately accrue eth- other diagnostic tests were done at a closer local facility nic minorities (OR 0.7 with respect to white patients provided it is certified as per national requirements. in cancer clinical trials)10 and a potential explanation The ability for tests to be carried out outside of the is that travel burden to centres mandated by specific trial centre perhaps should be continued and inte- trials (eg, rare cancers) implies time off from work grated into clinical trial procedures—at least for some and family commitments for both patients and careers safety blood tests that do not represent the primary leading to financial repercussions.11 Therefore, reduc- endpoint of the trial, and for radiological tests when a ing the frequency of in-­person visits could potentially centralised evaluation (Blinded Independent Central increase access to clinical trials participation and di- review (BICR)) is planned for progression-­free survival versity in recruitment. At present, several activities can end point analysis, or when overall survival is the main be potentially provided by electronic tools (informed objective of the study. Moreover, as a general strategy, consent discussion and signature, medical history col- methods and frequencies of safety assessments should lection focused on addressing eligibility criteria during be rationally determined in trial protocols taking into the screening procedures, evaluation of the quali- account preclinical and clinical safety data, be scien- ty of life and safety with electronic Patient Reported tifically and ethically justified and balanced with the Outcome (ePRO)) and this could be permanently ac- risks associated with hospital visits.15 Finally, the issue cepted in clinical trials procedures. The implementa- of funding needs to be addressed and the cost of these tion of telemedicine requires funding, user guidelines, extra hospitals’ procedures need to be traced and re- data protection integrity and management of reim- imbursed to the laboratories providing the procedures bursement policies. Lack of privacy and security stan- by the sponsor. This may be easier if research networks dards plays an important role in the legal challenges are established and oncologists and radiologists of pe- 2 Lorusso D, et al. ESMO Open 2020;5:e000924. doi:10.1136/esmoopen-2020-000924 Open access ripheral centres are trained as subinvestigators with the emergency, this model suggests that the obligatory delegated duties under the supervision of the main implementation of a national contract template, with study team.15 an agreed line listing activity costs and minimal local 4. Ethical Committee (EC) evaluation: the Italian sit- negotiations to meet hospital requirements, could uation. In Italy, there are 90 ECs actively evaluating dramatically speed up the global process of contracts trials and the median lead time between clinical trial leading to a faster opening of clinical trials and access application (CTA) submission and the site initiation for patients. The velocity in trial activation is not an visit (SIV) is 202 days (median EC evaluation time 152 obvious guarantee of trial success in terms of results days). Other studies report even longer duration reach- (Actemra/RoActemra phase 3 trial in ospitalized pa- ing up to 10–12 months for the whole process of trial tients with Covid-­ 19associated penumonia (COVAC- activation.16 During the emergency, AIFA (Italian Med- TA) trial is a clear example of this) but undoubtedly ical Agency) appointed a unique EC for evaluating all contribute to the efficiency of the system and would COVID-19 interventional studies and this dramatically be beneficial to all interested stakeholders, including reduced the time of approval (about 30 days between industry sponsors, the research sites and the patients CTA and SIV). The outstanding lesson we learnt is that who may ultimately benefit from participation in clini- is it not more deferrable the brave decision to identify cal cancer research. a single EC for trial (or at least for the area) to speed 6. Remote regulation audits: regulatory audits sponsored up the process of approval, particularly when looking by the authorities are essential to confirm the quality at the upcoming implementation of the European Por- and veracity of clinical data before placing a new mol- tal for CTA submission that imposes the identification ecule or new strategy at the disposal of patients. These of a central EC and defines strict times for evaluation. on-­site audits generally take an enormous amount of When the ClinicalTrials Directive (EUCTD) adopted preparation time, an attendance time that varies from in 2001 to facilitate and improve clinical research with- 3 to 5 full days and mobilises in addition to govern- in Europe is strictly followed, the median approval du- ment personnel, local teams and sponsor teams over ration is 59 days.17 Lastly, a simplification of approval many weeks. Again, the remote visits and remote con- procedures may translate in a significant reduction of trols as set up for certain studies during confinement the costs of submission: a Swiss trial reported a median could be an additional added value in the optimal or- time of 49 days and a median cost of 72.000 dollars for ganisation of tomorrow. the submission preparation of a randomised clinical 7. Data sharing and generosity: the example of the TER- trial to the authorities.18 AVOLT (Thoracic Cancers International COVID-19 5. Contract negotiation: the example of the tocilizum- Collaboration) registry. The idea to collect data on ab trial. Community-­based research programmes face mortality and disease outcome in patients with lung many barriers to participation in clinical trials, and cancer affected by COVID-19 was launched in March research contract and budget negotiations have been 2020 with a simple email immediately spread among consistently identified as time-­consuming procedures the international community involved in lung cancer and a barrier to study participation. American Society treatment, after the Chinese warning that the fatality of Clinical Oncology 's (ASCO) Community Research rate in patients with lung cancer was higher than in Forum conducted a survey about specific challenges other tumours. The TERAVOLT registry involved 21 in clinical research among 780 clinicians: 77% of the countries worldwide and was endorsed by a number respondents acknowledged barriers in the process of of international oncology societies and physicians who trial activation in terms of budget negotiation and le- accepted to collect and share data without any form gal review.19 After the publication of the survey, ASCO of financial support.20 In less than a month, data on recommended the standardisation of negotiation pro- 200 patients were collected and analysed, and actual- cesses and the creation of contract templates as neces- ly, more than 400 patients have been registered in the sary tools to implement the trial activation process.19 eCRF. The scientific community realised that, aside During the pandemic, the National Cancer Institute of from individualism and personal academic glory, the Naples promoted a therapeutic trial with tocilizumab necessity to collect data to take better care of patients in patients with COVID-19. The drug was supplied free with lung cancer was a priority and responded prompt- of charge by the drug company, an electronic CRF for ly. In the era of big data and learning machines, the data entry and drug order was created on the web sys- generous and altruistic sharing of knowledge and data, tem of the coordinating centre assuring drug delivery could represent an unimaginable step forward and an in 24 hours, and a single contract was signed between unprecedented turning-­point in the treatment of can- Agenzia Italiana del Farmaco (AIFA) and industry cer. without any administrative acts required at peripheral 8. Meetings: during the COVID-19 era, the majority of re- centres. The fortuitous combinations of all these facil- search conferences have been cancelled or postponed ities translated in the opening of 600 centres in less on an unparalleled scale, and attendance at confirmed than 3 weeks. Aside from the exceptional circumstanc- meetings is likely to be lower than expected due to es of a trial using a drug reducing ICU necessity during the fear of the disease. Basically, all the international Lorusso D, et al. ESMO Open 2020;5:e000924. doi:10.1136/esmoopen-2020-000924 3 Open access congress that took place in the last 4 months as ASCO, Contributors Authors provided equal contribution to the conception, writing and ESMO breast, AACR and Society of Gynecologic final approval of the paper. Oncology (SGO) were performed remotely and rep- Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-­for-­profit sectors. resented a great success with more people attendant remotely than on-­site, reduced time away from the hos- Competing interests None declared. pital for the physicians, less cost and carbon footprint. Patient consent for publication Not required. Nevertheless, besides the current emphasis on online Provenance and peer review Commissioned; externally peer reviewed. formats, we must honestly recognise that about half of Open access This is an open access article distributed in accordance with the the global population has no internet connectivity.21 It Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-­commercially, is time for the global scientific community to recognise and license their derivative works on different terms, provided the original work is the challenges that our less fortunate colleagues regu- properly cited, any changes made are indicated, and the use is non-­commercial. larly face and capture this exceptional opportunity to See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. build a more equitable global community for the scien- tists of tomorrow. REFERENCES 1 Liang W, Guan W, Chen R, et al. Cancer patients in SARS-­ CONCLUSION CoV-2 infection: a nationwide analysis in China. Lancet Oncol This pandemic has represented an unparalleled threat 2020;21:335–7. 2 Ueda M, Martins R, Hendrie PC, et al. Managing cancer care during for all of us, but also a tremendous opportunity for the COVID-19 pandemic: Agility and collaboration toward a common gaining a new vision in the world of clinical research. goal. J Natl Compr Canc Netw 2020:366–9. 3 Tagliamento M, Lambertini M, Genova C, et al. Call for ensuring COVID-19 has pointed out that sometimes, high level of cancer care continuity during COVID-19 pandemic. ESMO Open bureaucracy in research rules place unnecessary burdens 2020;5:e000783. 4 Poggio F, Tagliamento M, Di Maio M, et al. Assessing the impact on patients and clinicians and it suggests that it is time of the COVID-19 outbreak on the attitudes and practice of Italian to alleviate bureaucracy and introduce some practical oncologists toward breast cancer care and related research activities. JCO Oncol Pract 2020:OP.20.00297. changes into research organisation that will possibly 5 Hollander JE, Carr BG. Virtually perfect? telemedicine for Covid-19. promote patient access to trials and reduce the costs of N Engl J Med 2020;382:1679–81. 6 Doshi A, Platt Y, Dressen JR, et al. Keep calm and log on: the clinical research. Nevertheless, it is of utmost impor- telemedicine for COVID-19 pandemic response. J Hosp Med tance to underline that bureaucracy alleviation does not 2020;15:301–4. mean laxity with dramatic consequences on the quality 7 Padala PR, Jendro AM, Padala KP. Conducting clinical research during the COVID-19 pandemic: investigator and participant and consistency of clinical research and a careful balance perspectives. JMIR Public Health Surveill 2020;6:e18887. needs to be maintained between the simplification of the 8 Flodgren G, Rachas A, Farmer AJ, et al. Interactive telemedicine: effects on professional practice and health care outcomes. Cochrane procedures and the reliability of data. Database Syst Rev 2015:CD002098. Moreover, it is time to remember to ourselves that 9 Larson JL, Rosen AB, Wilson FA. The effect of telehealth interventions on quality of life of cancer patients: a systematic review it is patient care, not personal glory, that provides a and meta-­analysis. Telemed J E Health 2018;24:397–405. sense of meaning in our roles, and to reconsider a 10 Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-­based disparities. JAMA more generous approach in sharing information with 2004;291:2720–6. colleagues in order to build a robust scientific commu- 11 Borno HT, Zhang L, Siegel A, et al. At what cost to clinical trial nity of tomorrow.22 enrollment? A retrospective study of patient travel burden in cancer clinical trials. Oncologist 2018;23:1242–9. Given that the pandemic and its consequences are 12 U.S. Department of Commerce the Department of health and unlikely to dissipate soon, the time is arrived to funda- human services, National telecommunications and information administration, 1997. Available: https://www.​ntia.​doc.​gov/​legacy/​ mentally rethink study designs and procedures in order reports/​telemed/​cover.​htm to optimise clinical cancer research. Moreover, robust 13 Men J. Lack of reimbursement barrier to telehealth adoption, 2015. Available: https://www.​ajmc.​com/​newsroom/​lack-​of-​reimbursement-​ adaptations could make the field more resilient to future barrier-​to-​telehealth-​adoption pandemics The extent to which changes should be imple- 14 Uren SC, Kirkman MB, Dalton BS, et al. Reducing clinical trial monitoring resource allocation and costs through remote access to mented will vary by trial type and phase and although it electronic medical records. J Oncol Pract 2013;9:e13–16. could be easier to maximise translatability to routine prac- 15 Doherty GJ, Goksu M, de Paula BHR. Rethinking cancer clinical trials for COVID-19 and beyond. Nat Cancer 2020;29:568–72. tice for a phase III trial with a standard arm comparator, it 16 McNay LA, Tavel JA, Oseekey K, et al. Regulatory approvals in a would be more challenging for a first in the human study large multinational clinical trial: the ESPRIT experience. Control Clin with new class agents.15 Trials 2002;23:59–66. 17 Lambers Heerspink HJ, Dobre D, Hillege HL, et al. Does the All these relevant changes will require a profound European clinical trials Directive really improve clinical trial approval renewal of our tight global structures. However, if we time? Br J Clin Pharmacol 2008;66:546–50. 18 Speich B, Schur N, Gryaznov D, et al. Resource use, costs, and have the will to have all innovative changes in place in approval times for planning and preparing a randomized clinical a proper time frame and sharing a common vision and trial before and after the implementation of the new Swiss human research legislation. PLoS One 2019;14:e0210669. mission on research, then we will be creating a new era in 19 Thompson MA, Hurley PA, Faller B, et al. Challenges with research clinical research. The WHO has encouraged all of us to contract negotiations in community-­based cancer research. J Oncol Pract 2016;12:e626–32. think innovatively23 and as Walter Disney said ‘if you can dream it, you can do it’. 4 Lorusso D, et al. ESMO Open 2020;5:e000924. doi:10.1136/esmoopen-2020-000924 Open access 20 Garassino MC, Whisenant JG, Huang L-­C, et al. COVID-19 in patients 22 Fukushima M, Austin C, Sato N, et al. The global academic research with thoracic malignancies (TERAVOLT): first results of an international, organization network: data sharing to cure diseases and enable registry-­based, cohort study. Lancet Oncol 2020;21:914–22. learning health systems. Learn Health Syst 2019;3:e10073. 21 M PAD. Americans ’Internet Access: 2000-2015. Available: https:// 23 World Health Organization. WHO Director General’s opening remarks www.​pewresearch.​org/​internet/​2015/​06/​26/​americansinternet-​ at the media briefing on COVID-19 – 11 March 2020. Geneva: WHO, access-​2000-​2015/ [Accessed 15 Apr 2020]. 2020. Lorusso D, et al. ESMO Open 2020;5:e000924. doi:10.1136/esmoopen-2020-000924 5