On 30th January 2020 the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a public health emergency and on 11th March 2020 the pandemic [1]. Because of COVID-19 airborne transmission, the only effective measures to prevent COVID-19 community spread were social distance, containment, testing and isolating cases [2].

During the first phases of the pandemic, guidelines were established to limit the virus spread [3] and hospitals had to save personal protection equipment and resources in order to manage COVID-19 patients [4]. Pandemic deeply stressed the healthcare systems trying to preserve both patients and healthcare workers [5, 6].

Above all, cancer patients are a vulnerable population due to the immunosuppressed status caused by chemotherapy, radiotherapy or surgery and the consequent increased risk of infections [7]. Many COVID-19 guidelines have been released in the last two years to manage cancer patients, to reorganize healthcare services and professionals to fight and prevent spread of disease [7].

Despite all of the above, the virus spread so widely within hospitals and patients experienced anxiety and fear of contagious disease in a place that should have been considered safe and healthy [8].

Therefore, to reduce the risk of COVID-19 infection in cancer patients, oncologists tried to reduce hospital visits, postponing appointments and delaying oncological treatment when applicable [9]. In addition to this, hospitalizations due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection adversely affected the prognosis of cancer disease [7].

Among cancer care, clinical trials were notably affected by COVID-19, too. Despite the fact that clinical trials represent an important tool in cancer care, institutions worldwide have decided to suspend clinical trials recruitment at the beginning of the pandemic [10]. The guarantee of patient safety and of data integrity were the keys consideration in deciding whether to interrupt or continue clinical trials.

The present review aims to analyze the impact of the COVID-19 pandemic on clinical trials and to identify strategies to guarantee new opportunities of care in the respect of good clinical practice (GCP) in a bad scenario.

The studies included in the present review were selected from PubMed/Google Scholar/ScienceDirect databases. We used the terms “COVID-19”, “Pandemic”, “Clinical Trial”, “GCP”, “Oncology”, and “Guidelines” to select papers focusing on the impact of COVID-19 in oncological clinical trials.

Article search was conducted independently by the authors. The following inclusion criteria were used to identify the studies:

(1).

Manuscripts on clinical trial including original research, retrospective studies, observational studies, review articles, surveys, and guidelines.

In addition, the search engine clinicaltrial.gov was used to access clinical trial data.

The considered time was the pandemic starting from the 30th of January 2020 that is when the WHO proclaimed COVID-19 a public health emergency.

Exclusion criteria were:

(1).

Meeting or conference abstract only.

The flowchart of this study is shown in Figure 1.

In the last 10 years, clinical research of new cancer drugs plus better surgery techniques, radiotherapy and supportive care have all contributed to cancer patients’ increased survival [33].

The COVID-19 pandemic had an important impact on clinical research and on the development of new drugs especially during the first phase of a pandemic when recruiting was halted. When considering the pandemic scenario, two issues arise: is there any difference between cancer patients in clinical trials and standard patients? How long a clinical trial enrollment may be postponed?

Many literature data demonstrated that clinical trial patients have better outcomes for the superior clinical procedures [31]. Moreover, in order to be enrolled and satisfy all inclusion criteria (without exclusion ones), patients must have ideal clinical conditions. As a result of postponing enrollment, patients may worsen their conditions, become ineligible for the trial and lose the new drug opportunity [34]. Furthermore, sometimes enrollment in clinical trials may be the last chance for patients if there is no more therapy available [31]. With suboptimal treatments, cancer patients might have an increased risk of death regardless COVID-19 disease [34].

However, clinical trials are often available only in select accredited cancer centers and need more frequent in-person visits than standard treatments. During the pandemic, to limit travel and virus spread, sites began to guarantee, when available, virtual visits according to the new regulatory agency’s guidelines [35].

Since the beginning of the pandemic the use of telemedicine has increased more and more and its use continues even in a better pandemic condition. Telemedicine could be used for remote visits, but also to manage patients’ symptoms and adverse events [36]. Furthermore, telemedicine allows patients to not travel to clinical trial sites decreasing expenses and absences from work: this may contribute to an increase in participation in clinical trials [33]. On the other hand, telemedicine leads to a loss in a physician-patient relationship. In-person visits provide with greater privacy, improved communication between oncologists and patients and the opportunity to empathize, resulting in a trusting relationship and elderly patients may lack the skill to use technology and an internet connection [37, 38].

Before the pandemic, blood samples could not be tested outside of the trial site or in affiliated and certified laboratories. During the COVID-19 pandemic the regulatory agencies were more flexible and agreed on procedures to facilitate both patients and physicians allowing the use of unaffiliated laboratories [12].

Imaging studies endured modifications too. Clinical trials required high imaging’ frequency to evaluate the disease status in a timely manner [33]. During the pandemic, it was frequently necessary to delete or to delay imaging due to the radiologists or the patientsʼ difficulties: regulatory agencies and sponsors did not consider these events protocols’ deviations. Delay imaging could represent a significant improvement for patients in the future, decreasing their exposure to radiation and iodinated contrast. Thus, the usefulness of such close imaging might be evaluated against the use of possibly non-surrogate endpoints without compromising clinical trial data and results [33].

Research system required to be modified and re-adjust to guarantee the re-start or continuations of clinical trials [33]. Through the use of remote site visits and monitoring, the approach to trials has been significantly changed and simplified, saving both investigators and administration time and consequently improving the performance of clinical trials units and the quality of patient care [25].

It seems that the pandemic impact on clinical research will cause an increase in cancer deaths as a result of missed screening, delayed diagnosis and reduced oncology care.

In addition, significant implications for future outcomes and drug development will be apparent due to the reduction of enrollment in clinical trials in the first phase of the pandemic. Nevertheless, the pandemic offered an opportunity for clinical trial innovation, emphasizing aspects that could be simplified, modernized, and adapted in order to maintain research quality and integrity [37, 38].

Longer follow-up will be required in the future to analyze the post-pandemic impacts on clinical studies, including objectives, and outcome measures.

In conclusion, the COVID-19 pandemic changed many aspects of oncology care and will leave long-term consequences especially for clinical research. Among all modifiers, investigators would prefer to maintain the positive ones such as pragmatic and simplified trial designs and protocols, reducing in-person visits when not necessary and to minimizing sponsor and CROs visits. All of these elements would enhance clinical trials management. The pandemic provides an opportunity to focus on what is required, effective, and relevant for cancer patients, healthcare workers, and cancer drug development.