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Table 1 Qualitative spectrum of challenges and potential solutions in the review of COVID-19 trial proposals by research ethics committees (RECs)

From: Challenges and proposed solutions in making clinical research on COVID-19 ethical: a status quo analysis across German research ethics committees

Ethical principles Challenges
(sub-categories with examples of original responses)
Potential solutions
(sub-categories with examples of original responses)
Social value Lack of coordination/structures in study planning
Frequent simultaneous planning of several COVID-19 studies within an individual hospital and uncoordinated submission of studies to the local REC
Large number of small studies that partly overlap thematically and are often poorly structured
Lack of concrete objectives
Coordination
A multitude of studies could be coordinated at the institutional level
Priority setting
The urgency of studies in the current pandemic situation should be balanced. Several projects could be carried out retrospectively. More detailed assessment of the expected knowledge gains should be performed
Scientific validity Insufficient information for RECs
Scarce or incomplete proposals or study protocols
Frequent lack of biometrics
Insufficient disclosure of the funding
Lack of detailed description of data management or the consent process (for non-AMG/MPG* studies)
Difficulty evaluating valid/relevant endpoints when the knowledge of the disease is still uncertain, leading to difficulties in calculating sample sizes
Poor, provisional study planning/lack of clear objectives/insufficient statistics
Study protocols with the character of a rough sketch
Lack of clear rationale
Lack of documentation of independent factors influencing the outcome of the study
Insufficient number of planned study participants
Questionable study design selected for proof of efficacy
Poorly prepared and elaborated surveys/registry studies
Unclear length of the study (e.g. patients should be included as long as the pandemic lasts)
Frequent requirement of revisions/changes to primary and secondary endpoints
Lack of clarity regarding whether the proposal reflects a clinical study or experimental treatment according to national law (“individueller Heilversuch “)
Provision of statistical advice in advance rarely possible
In interventional studies, frequent inadequacy of sample size calculations (e.g. initially only small sample sizes, which are then continuously increased)
Lack of applicant knowledge of which guidelines they should follow
Better information
Requests from experts (e.g. for suggested biometrics) and additional REC meetings to discuss proposals in detail could be adopted
Studies could be subdivided into one main study with the possibility of submitting (ethically more problematic) sub-studies via amendments
If the essential aspects of the trial are evident from the proposal documents and there are no fundamental concerns, a positive vote with comments is given, indicating which aspects still must be supplemented in the study protocol
Pragmatic assessment of initial proposal could be tolerated if an interim evaluation were planned
Improvement of study planning and advisory process
Documents could be prepared with the help of institutional core facilities for clinical studies
Telephone/online advice could be offered
In REC counselling, a focus could be placed on scientific aspects, and (if possible) proposal formalities could be reduced
A statistician could be involved; an analysis plan and clear research objectives could be required
Additionally, the REC chair could contact principal investigator/sponsor for quick clarification of questions/problems
COVID-19-specific assistance with the application process could be offered
The REC should contact statistician before voting
If there are too few COVID-19 patients locally, multicentre studies with a sufficient number of patients could be required
Informed consent Informed consent for patients unable to give consent
For intensive care patients, a lack of an informed consent process, with the reasoning that these patients for the study are unable to give consent (according to national law: § 9 para. 2 GDPR)
Lack of clarity regarding how patients can be included in clinical studies when no patient-representative is appointed or available
Acceptance of verbal consent by some studies
Inability to give consent, even among non-intubated patients, due to the severity of the disease
Unclear whether additional, explicit consent for taking biospecimens should be required
Processing of consent via telephone without a description of documentation and verifiability
Problems obtaining consent from caregivers if they are not allowed to come to the hospital
Restricted possibility of consulting/informing relatives due infection control measures
Lack of permission for consent document to leave the patient’s room due to infection control measures
Formal problems with consent
Partial unavailability of patient information
Lack of comprehensibility, unclear wording,
Lack of information about data protection
Too many AMG/MPG* amendments; difficulties ensuring that the content is checked
Alternative forms of consent
Patients unable to give informed consent may be presented with the documents after they have gained the ability to give consent
Consent can be given by legal representatives; additionally, subsequent signatures of the legal representatives by post or fax should be considered
More detailed description in the study protocol of the process of including patients who are unable to give consent could be provided
For pure data collection where only clinical routine data are to be collected for secondary use, there is no time pressure. In this case, it is possible to wait until the patient is either able to give consent again or a legal representative who can give consent has been identified. The data can then be entered retrospectively as soon as consent has been obtained. If the patient were to die in the meantime, the data could be recorded anonymously
In the case of deceased persons, samples could be required to be anonymous, and no identifying research (whole or partial genome sequencing) would be carried out
A photo of the signed consent form can be archived outside the patient room
Formal improvement
Comprehensibility could be improved, and information about data protection should be added
REC should provide support and advice on all consent-related points
In addition to individual REC advice, European and national recommendations are given to sponsor/applicant
The necessary clarification documents could be archived
Sometimes, re-submission should also be required
The collection of data, samples, images, etc., could be enabled in crisis situations without consent according to national Infection Protection Law
Respect for participants   Improved data management
Secondary use of only anonymized data at the end of the usually relatively short course of the disease would also make informed consent unnecessary
Regarding biobanks, the proposed project could be restricted to COVID-19 and infectious diseases. Additionally, consent to anonymization after the end of the study/use for non-specified research projects should be obtained
Independent review Lack of time/time pressure
Co-counselling of the locally responsible REC in case of significantly shortened deadlines for COVID-19 studies
Applicants' expectation of rapid feedback
Intensive workload
Lack of courses/training for PIs due to infection protection measures
Frequent emergency staffing of RECs
Better time management
Those reviews of proposals on non-COVID-19 topics could be postponed that are required by the National code for physicians
In multicentre studies, after several unsuccessful attempts to contact other responsible RECs, assessment should be performed without their involvement
In multicentre-studies, additional claims from RECs responsible for secondary research sites are formulated as a suspensive condition
Consultation outside the usual deadlines and additional meetings could be conducted while maintaining the usual quality of consultation
Prioritization of proposals could be adopted
With regard to the investigators’ courses, more tolerance might be necessary, with at least temporary acceptance of online courses
Communication with the REC members could be performed via a web-based cloud instead of regular physical jour fixes
Communication with applicants could be performed via e-mail and short-term review by chairperson
Non-interventional clinical studies could be reviewed with secondary importance. Most of their questions can also be approached slightly later
Favourable risk–benefit ratio Uncertainty about the disease
In the case of interventional trials, difficulty regarding uncertainty about the disease because there is little preliminary data available or the situation is constantly changing, leading to a necessity for a certain degree of extrapolation
Difficulty of assessment due to the heterogeneous clinical picture
Limited benefit assessment due to the currently insufficient knowledge about the "natural course" of the disease
Amount/frequency of blood samples insufficiently justified
Reduction in the amount/frequency of blood samples
For blood tests, consent to use residual blood from routine examination could be obtained (after the patient regains the ability to give consent)
Fair participant selection Inclusion and allocation criteria
Unclear rationales for the exclusion of certain COVID-19 patient groups
Planning of several clinical studies despite the limited availability of hospitalized COVID-19 patients: How to allocate patients? Based on what criteria?
Vulnerable populations
Increasing number of studies exclusively with clinical and nursing staff
Protection of vulnerable populations
Statements on the careful handling of particularly vulnerable occupational groups in this critical situation could be made