Oncology Clinical Trials During the COVID-19 Pandemic

Lara Gongora is currently a medical oncologist and preceptor of the Medical Oncology Fellowship at Hospital Sírio-Libanês, São Paulo, Brazil.

Jardim is a medical oncologist at Hospital Sírio-Libanês in São Paulo, Brazil. He is currently the head of clinical research at Sírio-Libanês and coordinator of oncology at the Hospital Unit in Itaim.

Bastos is a genitourinary oncologist at Hospital Sírio-Libanês and Instituto do Cancer do Estado de São Paulo (Sao Paulo Cancer Institute), Brazil. He is currently the chair of the genitourinary branch of the Latin American Cooperative Oncology Group.

Key Points

• The coronavirus disease 2019 (COVID-19) pandemic has rapidly spread all over the world in the past several months. No effective treatment for COVID-19 has been established due to the lack of high-quality randomized studies. High transmissibility and considerable mortality rates have forced many national governments to implement quarantine measures.
• Many cancer patients rely on clinical trials to receive their oncologic care, but the routine conduct of clinical trials has substantially changed due to the COVID-19 pandemic. This will likely interfere with research and patient outcomes.
• The oncology research community should implement formal policies based on the guidance given from regulatory agencies, with the goal of minimizing the risks of COVID-19 infection while maintaining appropriate oncologic treatments for patients during this pandemic.

Introduction

As of June 2020, coronavirus disease 2019 (COVID-19) has affected almost 7 million people globally and caused more than 400,000 deaths worldwide.1 In addition to those lives lost to COVID-19, there have been innumerable consequences to patients who have not contracted the virus but suffer from other serious conditions, such as cancer. Although data published so far have included relatively small numbers of patients, cancer seems to be a risk factor for contracting COVID-19, and patients with cancer could be at a higher risk for poorer outcomes.^2,3

Fearing the potentially fatal consequences of COVID-19, patients with cancer, and institutions treating patients with cancer, have adopted measures to minimize potential exposure within cancer centers and hospitals. Most oncologists have elected for their patients to have, when possible, less intensive treatments; have delayed nonurgent treatments; have moved outpatient consultations away from general hospitals; and have made other tactical decisions to reduce risk. Ultimately, clinical management should be individualized for each patient based on a risk–benefit assessment of the oncology treatment in question, and priority should be given to those therapies offering overall survival gain and/or clear improvement in quality of life.^4,5

Clinical trials currently play an essential role in cancer care. This is especially true for patients who do not have access to novel oncology treatment modalities, such as immunotherapy or targeted therapy, or who have exhausted available standard-care options but still have a good performance status.⁶

However, the care of a clinical trial enrollee is much less flexible than that of a patient receiving standard-of-care treatment. For instance, oncology clinical trials may require more in-person hospital visits for safety monitoring, more imaging, and more frequent laboratory testing. These requirements present concerns for patients, institutions, and sponsors alike during this pandemic.⁷

The number of oncology clinical trials that are open for recruitment has significantly decreased over the past months of the pandemic. Between February and May 2020, 920 interventional oncology trials were interrupted due to COVID-19.⁸

We performed a search in clinicaltrials.gov using the keyword “cancer” and filtering for interventional studies (clinical trials) with a recruiting status. We compared the number of recruiting cancer trials in 2 periods: January to May 2019, and January to May 2020. From January 1, 2020, to May 31, 2020, we found 817 clinical trials involving cancer, compared with 1405 during the same period last year. This represents a 41.8% reduction of the recruiting clinical trials in oncology (Figure 1).

Figure 1. Effect of COVID-19 on Recruiting Oncology Trials.

In this review, we will discuss the main aspects of cancer clinical trial activities that have changed during COVID-19 pandemic, along with recommendations from regulatory agencies. The Table summarizes the US FDA and the European Medicines Agency (EMA) guidance on the management of clinical trials during this time.

Table. Summary of the US FDA and European Medicines Agency Guidance on the Management of Clinical Trials During the COVID-19 Pandemic.

Challenges to Clinical Oncology Trials During the Pandemic

The difficulties faced in keeping all phases of cancer clinical trials active are undeniable. For example, Tarantino et aldescribed the new routine of phase 1 studies at the European Institute of Oncology in Milan; Italy has been among the countries most affected by COVID-19. A major priority to maintain patient safety has involved decisions around the accrual of new patients, continuation (or not) of treatment for patients already enrolled, and alternate ways of monitoring. Additional training was provided to staff. Only the most necessary in-person activities were allowed at the hospital. Due to quarantine, patient access to the main trial site was also largely prohibited. In accord with the sponsors, it was decided to move radiological and biochemical studies to facilities nearer to patients’ homes, with central review of the scans. Furthermore, optional biopsies were temporarily withheld, and oral drugs were delivered to patients’ homes.⁹

Also recently published was an account of the multicenter, phase 3 ASCOLT trial, conducted largely in Asia The trial is evaluating aspirin vs placebo after standard adjuvant therapy for high-risk colorectal cancer, and the approach during the COVID-19 pandemic varied among centers in different countries. In some nations, recruitment was suspended, but the patients who were already enrolled continued taking the drug, with adaptations in safety monitoring, such as virtual visits by telephone. However, in Hong Kong, for instance, the study center pharmacy stopped delivering oral research treatments. Differences in the management of different patients enrolled in clinical trials during the pandemic raises the inevitable question of how the study’s final results will be impacted.¹⁰

Similarly, it is difficult to compare the conduct of clinical trials in different countries and regions, because the epidemiology of COVID-19 varies considerably.1 Although regulatory agencies have published guidance for sponsors and study sites, institutional differences must always be taken into consideration when analyzing the potential changes in clinical trials.¹¹

The American Society of Clinical Oncology (ASCO) conducted a survey to better understand the situation in 64 different American research programs. A total of 32 surveys were adequately answered and included in the analysis; 18 (56.25%) of them were nonacademic research centers. Of note, 20 (64.52%)institutions answered that a formal policy was developed for their own ongoing trials.¹²

Important Topics Involving Research Addressed by Regulatory Agencies During the COVID-19 Pandemic

Enrollment in oncology clinical trials

Numerous research centers have chosen to halt patient enrollment, and oncology has been among the most affected areas in terms of suspending, postponing, or making other changes in conducting clinical trials. A GlobalData report showed that as of April 8, 2020, (28%) of 389 disrupted clinical trials were in oncology. Of note, more than 50% of the disrupted oncology trials were focused on lung cancer, breast cancer, multiple myeloma, myelodysplastic syndrome, and prostate cancer.¹³

Screening and/or enrollment on any oncology clinical trial was halted in approximately 25% of US research centers. Priority for continued enrollment has been given to trials with lower risk and higher safety profiles, such as those with shorter infusion times, easier schedules, and less pharmacokinetic testing.¹²

Another analysis combined results from a survey of 36 investigators conducting oncology clinical trials worldwide, and data from IQVIA and clinicaltrials.gov; these results were consistent with previously published data. Only about 20% of institutions in the United States and about 14% of those in Europe were pursuing active normal trial enrollment. In Asia, 60% of institutions had active enrollment at the time of the survey; this relatively high number was presumably attributable to the decline, at the time, of the number of COVID-19 cases locally. Key factors involved in the decision to enroll patients in clinical trials were patient care and therapy type, but the institutions also considered such other important factors as line of treatment, patient performance status, and indication of treatment. These factors will also be considered in future clinical trials, according to the survey.¹⁴

Sponsors should carefully evaluate the feasibility of enrolling patients into ongoing clinical trials and of beginning new clinical trials. Risk vs benefit of new or continued accruals should be discussed with the staffs at investigational sites.¹⁵

Figure 2. Oncology Clinical Trials During COVID-19 Pandemic

Remote methods in clinical trials

The regulatory agencies have addressed and offered guidance regarding the use of remote methods in clinical trials. The EMA notes that on-site monitoring visits could be cancelled or postponed. Remote monitoring and source data verification should be reserved for crisis periods. Telemedicine could be used for checking adverse events, for instance. Importantly, in-person patient visits should be restricted to urgent situations when there are no good alternatives. Visits with the sole purpose of obtaining re-consent should be avoided; this should be accomplished remotely.¹⁵

The US FDA recognizes that alternative ways of monitoring could result in delayed identification of protocol deviations or could impair compliance with the Good Clinical Practice standard. While the FDA acknowledged that remote methods can be used both with patients and sponsors to optimize clinical trials and minimize possible exposure to coronavirus,¹⁶ they also pointed out that access to remote technologies differs among patients, and patients’ disabilities must be considered when planning telemedicine consultations. Other regulatory agencies have also recommended remote patients’ safety evaluations and remote site monitoring during COVID-19 pandemic^.11,17

Approximately 90% of the American research centers that participated in the ASCO survey were adopting remote patient review of symptoms, and 75% of study staff members were also working remotely. In more than 60% of the centers, remote methods were used as well for site initiation visits, sponsor monitoring, and/or other clinical research activities. Interestingly, most of these measures were initiated by the research site. A challenge of remote communication in clinical trials was the time spent preparing for and conducting the telehealth visits. Nevertheless, the majority of the institutions will consider telehealth visits, remote site initiation visits, and remote monitoring as suitable alternatives for clinical trials in the future, post COVID-19.¹²

In addition, of 22 investigators interviewed on this topic in a recent Nature Reviews paper, the overwhelming majority (82%) also stated that telemedicine is or will be an important strategy to be utilized in clinical trials during this pandemic.¹⁴

Any use of new remote technologies in conducting trials must consider patients’ rights to privacy and data confidentiality. In addition, virtual consultations should be as complete as possible and, when imaging or laboratory studies are performed in other than the usual facilities—ie, those nearer patients’ homes—it is crucial to review the results carefully to assure patients’ continued safety.¹⁸

Distribution of investigational products

Depending on where a patient resides, traveling to a research center for an investigational therapy may be a challenge. Therefore, regulatory agencies have allowed new delivery methods for some drugs, such as ones distributed for self-administration. FDA has also mentioned planning for alternative administration for drugs that are normally administered in a health care facility, utilizing visiting nurse services, for instance, or even creating alternate sites run by nonstudy staff.¹⁶

In addressing drug supply, EMA has stated that distributors can deliver drugs directly to a patient if their supply runs out. However, this shipment should be described in a contract between the distributor and the sponsor. The investigator must explain the procedures to trial participants and obtain their verbal consent, which is then documented in the patient’s medical record. These procedures should not compromise trials’ blinding and compliance with randomization.¹⁵

In all cases, safety must be ensured. If necessary, trial participants, and/or their caregivers, must be trained in handling their medications.

Protocol deviations

A higher probability of protocol deviations exists during this pandemic. Almost 40% of the institutions surveyed by ASCO considered protocol compliance to be a challenge,¹² and several ethics committees are currently focusing on protocol deviations.¹⁴ Investigators are concerned that protocol deviations would cause unsolved queries.

EMA recommends that sponsors periodically analyze interim trial results for possible deviations, and evaluate whether protocol amendments are needed. Every deviation should be included in the clinical study report.¹⁵

Normally, protocol amendments would go through institutional review board (IRB)/independent ethics committee (IEC) review. However, sometimes this process may not be possible due to the pandemic. FDA allows changes in the protocol without IRB approval to protect the life and well-being of trial participants, but in such situations, communicating with the IRB/IEC must be done as soon as possible. Any protocol deviations should be taken into account prior to locking a trial’s database.¹⁶ Because many activities of an IRB may be currently focused on clinical trials related to COVID-19, it is crucial that a constant channel exists to discuss protocol deviations in other trials. In many institutions, this has been or will be accomplished by teleconferencing.

Other relevant issues

Additional training and safety

With fewer staff members working on-site at research centers, those research staff and physician investigators who are present may need to take on additional responsibilities. They must receive adequate training, if necessary, to ensure patients’ safety.¹⁸

If possible, a study center should have a low-risk area specifically for patients participating in clinical trials, in which personal protective equipment must be worn and all safety measures are consistently enforced for every person (patient or staff member) involved in the clinical trial process. Screening of staff for COVID-19 symptoms should be considered.¹⁹

Patient education

The investigator should inform participants about any changes on clinical trials that could impact their care and scheduling during the study. Moreover, the study staff should adopt all procedures in accordance with regional or national policies to prevent and control COVID-19, and discuss these measures with patients.^15,16

Expenses

Unexpected trial expenses may accrue for a trial participant in this current scenario, and EMA recommends that sponsors cover them as soon as possible. via investigators.¹⁵

Screening for COVID-19

Screening for COVID-19 may become mandatory (by action of the health care system or the government) during the clinical trial. Should that happen, protocol amendment is not necessary, according to the FDA, unless these tests become a part of the research objective.¹⁶

Clinical study report

According to the regulatory agencies, the clinical study report must describe all contingency measures taken and all protocol deviations, and it must list all participants affected by COVID-19 and the severity of their illness during the trial.^15,16

Oncology clinical trials during the COVID-19 pandemic: the experience of a referral oncologic center in Brazil

Brazil is still experiencing the continuous rise of both number of new cases and deaths from COVID-19. As of June 8, 2020, 691,758 cases and 36,455 deaths have been recorded.^20,21 Like the FDA and EMA, Brazil’s regulatory agency, ANVISA, has published recommendations regarding the conduct of clinical trials during this pandemic, highlighting the importance of good clinical practice and patients’ safety. ANVISA’s main points include¹⁷:

1. The sponsors, along with investigators and the IRB/IEC, may decide whether a participant should remain in a clinical trial, based on potential risks and benefits to the participant.
2. Remote methods can be used for safety evaluations and monitoring.
3. ANVISA need not be notified of COVID-19 screening procedures as a protocol amendment, unless these tests will be part of the research objectives.
4. ANVISA need not be notified of protocol amendments made as a consequence of COVID-19, but the amendments will need to be described in the annual clinical research report.
5. Delivery of investigational products directly to patients’ homes, with adequate patient training, is allowed.
6. Protocol deviations should be considered before locking a trial’s database. If there is any chance that the deviations could affect final results, the sponsors must communicate with ANVISA.

In March 2020, our institution, Hospital Sírio Libanês, located in São Paulo, Brazil, created specific guidance for clinical trials conducted during this pandemic, mostly based on ANVISA’s guidance. Recommendations were made such that investigators, along with sponsors, could decide whether a protocol should be interrupted when there is no direct benefit to trial’s participants, adding the risk of coronavirus exposure. Trials that bring direct benefit to participants should be continued, and remote technologies should be employed as much as possible in such trials. Discussions about specific methods to minimize patients’ exposure should include remote technology for patient evaluation, delivery of oral drugs at patients’ homes, and any others that would be applicable. All such measures and protocol deviations should be reported to the hospital’s Ethics Committee in the annual research report. Suspension of the enrollment of new patients in clinical trials should be discussed. The clinical research staff should also discuss ways of minimizing their own exposure, such as working remotely.²²

Currently, most oncology clinical trials in our hospital have put recruitment on hold. Trials with a set start date were postponed. Research teams have been working remotely, for the most part, but patients who continue on clinical trials are still making in-person visits. We remain active in planning for the future, with feasibility studies ongoing for future trials. Regulatory staff are focusing on reviewing budgets and pending contracts. Teleconferences have been widely used in research meetings and, importantly, we have used this period to plan improvements in our research program.

Conclusions

COVID-19 has changed the international health care system in every single way. Consequently, oncology clinical trials have suffered, with a high rate of disruption. For the trials that continue, ensuring participants’ security is crucial. Regulatory agencies have formalized recommendations to help guide the research community. Research institutions ultimately should write their own guidance materials, considering their site’s COVID-19 epidemiology and access of staff and patients to technologies, and discussions with their trials’ sponsors and their IRB/IEC should be ongoing.

References

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15. Guidance on the management of clinical trials during the COVID-19 (coronavirus) pandemic. version 3. European Medicines Agency. April 28, 2020. Accessed June 30, 2020. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_en.pdf

16. FDA guidance on conduct of clinical trials of medical products during COVID-19 public health emergency. guidance for industry, investigators, and institutional review boards. FDA. March 2020. Accessed June 30, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency

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18. Tan AC, Ashley DM, Khasraw M. Adapting to a pandemic – conducting oncology trials during the SARS-CoV-2 pandemic. Clin Cancer Res. Published online April 20, 2020. doi:10.1158/1078-0432.CCR-20-1364

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Financial Disclosure:

Lara Gongora has nothing to disclose.

Jardim has received speaker fees from Roche, Janssen, Astellas, MSD, Bristol-Myers Squibb, and Libbs, as well as consultant fees from Janssen, Bristol-Myers Squibb, and Libbs.

Bastos has received research funding from Janssen, Astellas, and Pfizer, as well as honoraria and consulting fees from Janssen, Astellas, MSD, Bayer, Roche, and AstraZeneca.