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\begin{document}

\title{Guidance for Head and Neck clinical trials during COVID-19}



\author[1]{Pankaj Chaturvedi, MS, FACS}%
\affil[1]{Tata Memorial Center}%


\vspace{-1em}



  
  \date{May 21, 2024}


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\begin{abstract}
As this ever-evolving pandemic lays itself, more of its impact is being
understood. Until recently, most guidelines were reported to aid in
managing and treating suspected or confirmed cases. Research
institutions around the world are responding with a sense of confusion.
Some are continuing routinely, especially those who are overseeing
clinical trials that could offer life-saving therapies, particularly
against the novel coronavirus. Since research must continue even in the
face of a shutdown, we aim to collate the currently available
recommendations from various organizations and provide guidance to head
and neck researchers across the world during these trying times.%
\end{abstract}%



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\textbf{Authors:}

Arjun Gurmeet Singh, MDS

(Oral and Maxillofacial Surgery), MFDS (Glasgow)

Department of Head and Neck Oncology

Tata Memorial Center

Mumbai, India

Email: arjun193@gmail.com

Pankaj Chaturvedi, MS, FACS (Corresponding author)

Department of Head and Neck Oncology

Tata Memorial Center

Mumbai, India

Email: chaturvedi.pankaj@gmail.com

\textbf{Funding statement}

No funding was obtained from any sources.

\textbf{Conflict of Interest statement}

None of the authors have any conflict of interest to declare.

\textbf{Authors contribution statement}

All authors have made a significant contribution to this article from
concept to implementation and publication.{}

\textbf{Abstract}

As this ever-evolving pandemic lays itself, more of its impact is being
understood. Until recently, most guidelines were reported to aid in
managing and treating suspected or confirmed cases. Research
institutions around the world are responding with a sense of confusion.
Some are continuing routinely, especially those who are overseeing
clinical trials that could offer life-saving therapies, particularly
against the novel coronavirus. Since research must continue even in the
face of a shutdown, we aim to collate the currently available
recommendations from various organizations and provide guidance to head
and neck researchers across the world during these trying times.

Introduction

Various challenges exist for researchers during the Coronavirus pandemic
that are resulting from restrictions at healthcare facilities, changes
in availability of staff and unidentified possible interactions. Some
trial participants or investigators might also be required to
self-isolate or be infected by the severe acute respiratory
syndrome-like coronavirus-2 (SARS-CoV-2) causing a moral dilemma in
keeping trials running. Another issue specific to the head and neck
region is the proximity to the areas through which the virus can be
easily transmitted requiring further amendments to protocols and need
for additional equipment. Multi institutional trial conduct can also be
affected by the unavailability of Investigational Medicinal Products
(IMPs) due to the restrictions affecting supply chains across the world.
All these factors might have an impact on the accrual, assessment and
provision of clinical trials.

The impact of Coronavirus pandemic needs to be considered on ongoing and
new clinical trials. Sponsors need to take into account the national
guidelines and restrictive measures imposed including limitations of
trial participants and staff confinements and their ability to perform
visits, interviews and forms and notification of adverse effects.
Funding agencies and sponsors should be informed regarding the impact
the current situation might have on the trial protocol. Currently, most
of the trials are being run based on risk-benefit concerns and
contingencies present locally with the highest priority given to the
health and safety of the trial participants. In the event the
participant is unable to attend a scheduled visit, measures such as
virtual or tele contact may be required to identify ensure adequate
medical oversight. With all these limitations it is of utmost importance
to make provisions for data protection with adequate documentation. It
is also important to note that international publishers have made clear
that in the event of a public health emergency, information with
immediate health implications would be disseminated without any
restrictions. This document aims to collate the currently available
recommendations from various organizations and provide guidance to head
and neck researchers across the world during these trying times.

Initiating new trials

Regulatory bodies have currently paused approvals for non-COVID-19 new
trial registration unless requiring an expedited approval in the event
of public health emergencies with few also advising to withhold
enrollment.(1) The study team should critically assess the feasibility
of starting a clinical trial or enrolling new participants. The risk
benefit section of protocols should include the additional risks that
the participant and trial workers could encounter due to COVID-19 with
adequate risk mitigation measures. Most guidelines suggest a risk
assessment by the sponsor weighed against the anticipated benefit for
the participant and society before initiating enrollment.(2,3) In trials
especially of the head and neck cancer, where the participants enrolled
may be determined as being a risk group for COVID-19 or in trial that
involve increasing the risk to contract COVID-19 such as chemotherapy
related trials, should be carefully considered before starting or
continuing such trials.

Considerations for ongoing trials

Ensuring safety of trial participants is paramount and decisions should
be taken on an individual participant basis focusing on the potential
benefit. Decisions regarding further trial recruitment, continuing use
of IMPs for enrolled participants and need to change the monitoring
methods and site during an ongoing trial should be kept in mind. At any
stage, it is very important for participants to be kept informed of
changes to study and other plans that could impact their care.

\emph{How to obtain informed consent from patient in isolation?}

All guidelines suggest obtaining written informed consent before
enrolling patients. If this is not possible due to COVID-19 isolation
measures or safety, electronic methods should be considered.(4) If not
possible electronically, a three way call phone or video communication
with the investigator, patient and an impartial witness and/or if
requested, additional participants (e.g. next in kin, spouse, etc.) have
been suggested for verbal confirmation. If the signed consent form
cannot be collected from the patient, an attested copy by the witness
and investigator who participated in the call or a photograph of the
signed informed consent with attestation of the investigator should
suffice.(4) The details of the above procedure should be included with
the informed consent in the source notes for records.

\emph{Protection of participant and the investigators}

Clinical investigators and sponsors should consult their Institutional
Review Board (IRBs) or Institutional Ethics Committees (IECs) in
deciding if the participants' safety and rights are best served and
protected by participating in the ongoing study or by discontinuing the
IMP, intervention or even participation in the trial.

Most head and neck oncology trials are ongoing in an institutional setup
where preemptive measures to contain the virus are already instituted.
If the study is enrolling participants, provisions for investigator's
safety should be available at the site. If not possible, the sponsor
should choose to withhold further intervention or monitoring until such
safety measures are in place for the investigator.

\emph{How to report changes to the ethics committee?}

Most guidelines encourage sponsors and investigators to engage with
their local IRB/IEC as early as possible as emergent changes are
anticipated in protocols due to COVID-19.(1,2,4) Some sponsors may
choose to redesign their studies to require less labor, at the same time
in a way that salvages the study. The changes made to minimize the
hazard or protect the life and well being of participants and
investigators may be implemented without IRB approval before filing an
amendment, but are required to be reported later. The amendment needs to
include the specific protocol deviation and the reason for the
deviation. For example, specific visits conducted by virtual contact
rather than as specified in the protocol due to the current situation,
generally would be acceptable. For efficacy assessments, protocol
modifications are required for the collection of endpoints done via
methods alternate to the ones specified in the protocol such as virtual
assessments, delays and alternate collection of specimens.(4)

\emph{Are alternate forms of visit appropriate?}

Since trial participants may not be able to visit the site for the
protocol specific visits and investigations, sponsors should evaluate if
alternate measures such as virtual visits, alternate locations for
assessment, including imaging centers and labs, could suffice when
necessary, only after ensuring the safety of the participant. If an
in-person visit is necessary, it is the sponsors' responsibility to
assure the implementation of the monitoring safely.(2,4) This is
important for trials that include participants who no longer have access
to IMPs and who need additional safety monitoring (eg. for withdrawal of
an active IMP).

\emph{Should COVID-19 screening be reported?}

Some institutions might mandate screening all participants for COVID-19
as a protocol. This does not need to be reported or amended in the
protocol unless the testing data would be collected and used as a part
of a new objective in the study.(4)

\emph{Home delivery of IMPs}

Since the scheduled visits at the site may be significantly impacted,
certain IMPs that require self-administration may be amenable for home
delivery but should be documented. This may include infusions as well.
Where self-administration is not possible and monitoring is required,
alternate administration methods via home nurses or at smaller care
facilities may be planned after obtaining approval from the local
reviewing authorities. In all cases it is important to maintain IMPs
accountability before implementing any alternate methods.

\emph{Dealing with possible missing data and statistical analyses}

Due to the changes in scheduled visits or patient's discontinuation,
there may be missing information for the protocol specified procedures.
Nonetheless, it is important to capture all details in the case report
form that explains the basis of this missing information. This
information should be summarized in the study report. If changes in
protocol, including missing data, will lead to amending the data
collection and statistical analysis, the sponsor should consider
informing the local review board before locking their databases. A
pre-specified plan for analyses should be constituted to tackle the
protocol deviations related to COVID-19.

The need to apply new processes or to modify existing ones will vary
based on the protocol and local situation. Some considerations need to
be made whether it is appropriate to delay assessments for an ongoing
trial or to discontinue or withdraw participants if the study cannot be
properly conducted under the existing protocols.

It is important to keep the measures going that yield the most
information for the least effort and resources. Sponsors should describe
the measures instituted in view of the ongoing pandemic that may
include:

\begin{itemize}
\tightlist
\item
  Contingency measures to manage study conduct during disruption
\item
  Document and list all participants affected by COVID-19 and describe
  how the participation as altered
\item
  Analyze and discuss the impact of the contingency measures on safety
  and efficacy
\end{itemize}

References

1. Q\&A on the impact of COVID-19 on research funded or supported by
NIHR {[}Internet{]}. {[}cited 2020 Apr 16{]}. Available from:
https://www.nihr.ac.uk/documents/qanda-on-the-impact-of-covid-19-on-research-funded-or-supported-by-nihr/24467

2. guidanceclinicaltrials\_covid19\_en.pdf {[}Internet{]}. {[}cited 2020
Apr 16{]}. Available from:
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials\_covid19\_en.pdf

3. Research C for DE and. Clinical Trial Conduct During the COVID-19
Pandemic. FDA {[}Internet{]}. 2020 Apr 7 {[}cited 2020 Apr 16{]};
Available from:
https://www.fda.gov/drugs/coronavirus-covid-19-drugs/clinical-trial-conduct-during-covid-19-pandemic

4. FDA Guidance on Conduct of Clinical Trials of Medical Products during
COVID-19 Pandemic: Guidance for Industry, Investigators, and
Institutional Review Boards. :16.

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