Consent challenges.

Time pressure. Various interviewees emphasized that they needed to obtain the informed consent under increased time pressure. Often this was due to the “rapid deterioration of the health condition of patients” with COVID-19 (C1).

Quote (interview 14): “If you are the only person who can enroll a patient in a trial today, you have to do it today, because tomorrow the patient may not be able to give consent, or it may be too late”

Furthermore, interviewees indicated the need to “reduce contact time” to minimize the risk of infection (C2).

Isolation, physical distancing, and hygiene conditions. Various interviewees indicated “difficulties in building the doctor-patient-relationship” due to the intended contact restrictions and the protective clothing (C3). Within the strict isolation conditions, the “number of patient contacts” and the duration of these were reduced in order to minimize the spread of the virus (C4). In addition, it was highlighted that the “reduced accessibility to legal guardians” (C5) and the “contact restrictions for relatives” (C6) had negative impact on informed consent procedures.

Overburdening the patient. Interviewees reported several aspects of the pandemic situation that carried a risk to overburden the patient and thus weaken the quality of the informed consent procedure. Some patients were confronted with “parallel/competitive study recruitment” which could cause distress at the patient side (C7).

Quote (interview 6): “For example, doctor A goes to the patient and asks: "Would you like to take part in the XY drug trial? The patient asks for time to think about it. During the reflection period, Doctor B comes and clarifies for the next study. And the patient thinks it’s the same trial and says yes. These things can happen.”

Patients often had difficulties in “understanding due to complexity” of informed consent documents (C8). This was further complicated by the pandemic context.

Quote (interview 7): “Many were also sceptical (about participating in a study for a foreign disease such as COVID-19) […] they were often in a very bad condition and then overwhelmed by all the information you have to give them quickly”.

The informed consent procedure could especially overburden those patients that already suffered “severe symptomatology” and rapid disease progression (C9). Furthermore, some interviewees mentioned an “increased risk of therapeutic misunderstanding” when the disease is rather novel (C10).

Impact of consent challenges on clinical research.

Several interviewees reported that the challenges around appropriate consent procedures for COVID-19 trials had an impact on conducting clinical research.

Heterogenous ethics review. Some interviewees mentioned “heterogenous ethics review” (C11). One example given by interviewees was an IRB decision that required the exclusion from the trial of those participants who had initially consented but lost capacity during the trial due to disease progression. Other IRBs allowed these participants to remain in the trial.

Delay and recruitment failure. Interviewees pointed to the potential “delay” (C12) of conducting trials or even “stops/recruitment failures” (C13) that result, for example, from difficulties to contact legal proxies during a pandemic.

Bias. Interviewees further pointed to the risk that even in conducted studies the exclusion of critically ill patients due to consent limitations would “introduce important bias” (C14).

Quote (interview 16): “[…] if someone is unable to give consent at the beginning of the trial: For these patients, I think you have to do everything you can to include them in the trials, because otherwise you get an enormous bias if you leave out the seriously ill”

Potential strategies for consent challenges.

Opt-in consent as ethical standard in interventional studies. Despite the challenges experienced, several interviewees emphasized the informed consent and the self-determination of patients as the ethical standard with particular “relevance for interventional studies” (C15). In addition to patient-centered considerations, some interviewees addressed the protective function of the informed consent for potential “conflicts of interest” of clinician investigators (C16).

Quote (interview 3): “Never [change consent in times of crisis]! Doctors always have conflicts of interest.”

Consent models for secondary use of patient data. Regarding non-interventional studies, various interviewees suggested the implementation of a “broad consent model” for the use of routine data and biological samples (C17). The opportunity to learn immediately from routine care with legitimate access to routine data was emphasized. By pointing to the potentially high social value of secondary use of patient data during a pandemic interviewees suggested an “opt-out model” (C18).

Quote (interview 14): “[…] such an opt-out solution, I would not find it so strange for register studies”

Likewise, a “no consent model” for the secondary use of patient data was discussed (P19).

Quote (interview 11): “And I have to say, for this part, my impression at Covid-19 was that the interest for the general public is so great that it would be helpful to define at a high level what is generally possible for the general public and does not require consent"

Requirements for patients unable to give consent. When discussing how to better prepare for potential future pandemics nearly all interviewees expressed the need to implement strategies for those patients who are unable to give consent. Interviewees highlighted the “need of consistent IRB requirements” especially for study participants who lose their consciousness after prior consent (C20). Several interviewees described the “deferred and legal proxy consent” (C21) as an appropriate option. However they referred how difficult and challenging it is for relatives to make such a proxy decision on trial participation especially in a pandemic situation.

Quote (interview 1): “Well, I would not necessarily require deferred consent, but a combination of deferred consent and a consultant might make it better, yes; that someone from a different field actually has to look at it. I think in observational studies it’s relatively uncritical and in interventional studies I think it’s also appropriate”

Some interviewees mentioned the option of “alternative proxy decision maker” (C22) such as physicians or ethics committees.

Perceived benefits of prioritization.

Lack of explicit prioritization. Our study did not aim to gather quantitative information about how often our interview participants experienced explicit prioritization on which trials to conduct and which not. We want to highlight, however, that from all 21 interviewees engaged in conducting or coordinating clinical research all except one reported that they did not experience any type of explicit prioritization of clinical studies. Several interviewees stressing this “lack of prioritization” at the same time highlighted the different needs for prioritization as presented above (P10).

Quote (interview 5): “You’re offered something, you don’t have anything, and then you just take it, and sometimes there’s even overlap. So it’s problematic: We have multiple trials that are looking at the same patient population, and that’s a problem”

Ensuring patient protection. Interviewees described that if prioritization of clinical trials could help reduce unnecessary risks that might come with participation in less well justified trials this would support patient protection and thus “improve risk-benefit assessment” of planned clinical trials (P1).

Quote (interview 11): “[…] And then came the reconvalescent plasma trial. It is still running. And the impression is: […] Not only are we not making a ’benefit’, but we are prolonging the intensive care stay. We are rather creating problems. And finally, piece by piece, the studies came here that showed: "It doesn’t help there. It doesn’t help there. [..] When do you stop such a study? (Interview 11)”

Prioritization could also “prevent the overburdening of patients” that are asked by different physicians at the same time to participate in their clinical trials (P2).

Improving validity and efficiency. Interviewees mentioned the need to “reduce the number of parallel/redundant studies” that were conducted during the COVID-19 pandemic (P3). Several interviewees further highlighted that the designs of COVID-19 trials often lacked measures to increase the robustness and that the reporting quality of study protocols was low. A more explicit prioritization process might therefore “improve the quality of clinical trials” (P4) and could “avoid that trials are conducted with insufficient resources and expertise” (P5). As mentioned above, in some occasions one patient was asked to participate in several studies illustrating the benefit of prioritization measures to “reduce inefficiencies” due to competitive recruitment (P6).

Increasing relevance. Numerous interviewees pointed out that several research questions addressed in COVID-19 studies lacked relevance. Prioritization could therefore “support the relevance” of clinical studies (P7).

Quote (interview 2): “[…] this is indeed a problem and I would have liked the national side to have coordinated this and said that these and the studies have priority because they really take us forward and not the Xth study, which examines something but does not really bring a solution in terms of the pandemic”

Some interviewees commented on important criteria for prioritization and most of them mentioned clinical relevance as a top criterion. Some interviewees criticized that most studies investigated different drug treatments and only few procedures for COVID-19 such as lung ventilation. Therefore, more explicit prioritization could not only select among already planned studies but also “identify patient-oriented knowledge gaps” (P8). Interviewees mentioned that prioritization also becomes relevant in “allocating the scarce resource of biological samples” such as lung tissue from patients with COVID-19 (P9).

Potential strategies for prioritization.

Central coordination and collaboration. Interviewees repeatedly emphasized that central coordination via, for example, a “national board” (P11) and “national cooperation” (P12) could be helpful to prioritize clinical studies.

Quote (interview 11): “[…] it would have been really helpful, as people have said in the past, if a committee had been set up very quickly and had had time to really get to know each other. Maybe even nationwide and would have said: "These are really the best candidates. These are the ones we’re counting on".

The RECOVERY trial [12] and other WHO studies were mentioned as having created relevant evidence via respective coordination and collaboration efforts. In order to profit from the specific expertise and study ideas at individual university hospitals interviewees proposed a “central registry” (P13). Another interviewee suggested the development of a procedure for “ad-hoc expert groups” (P14). This ad hoc expert groups should be set up for specific urgent topics with members from different institutes that jointly discuss and design a specific study. Interviewees highlighted that central coordination could also improve “efficiency in study planning” (P15) on a national level that might allow Germany to better participate in international activities such as the WHO studies. Furthermore, central coordination was also mentioned as a way to support “effective recruitment of special patient-groups” (P16). Additionally, interviewees highlighted that the “management of conflict of interests” could be supported by more central coordination and collaboration (P17).

Adapting study design. Interviewees mentioned that study designs like “multicenter study” (P18) could be helpful to improve recruitment and efficiency:

Quote (interview 16): “There are three studies running in parallel […]. And of course it would be helpful to combine them, because the number of cases and the range of people included is getting larger. The background of the participants also depends on whether I am in a practice at the university hospital or in a peripheral hospital, but we have not been able to bring the participants together.”

Others mentioned that “adaptive study designs” (P19) could further address the need of better coordination in line with the need for prioritization: “then they just need a fixed established therapy group, such as ACTT [Adaptive COVID-19 Treatment Trial], where a joint design is then developed under fixed coordination, but there must then also be a team behind it” (Interview 18).

Alignment with funding. While discussing the issue of prioritization, different interviewees mentioned a lack of public calls for therapeutic studies. Prioritization should align with opportunities for “funding priority studies” (P20) and “calls for priority topics” (P21).

Quote (interview 4): “There is no funding because there is no pharma. There is no funding because there is no virology, no basis in it, but it is a purely clinical issue. I would like to see a central committee. That’s where the questions would come from. Then you say these are the ’most important’ questions for us that need to be answered”

Effective prioritization is further dependent on “efficient funding procedures” (P22) and “fair funding procedures” (P23). The fairness of funding was also contextualized as a consequence of more explicit prioritization if the relevance of certain research questions receives more priority than for example the size of a university. “Sustainable funding” (P24) becomes according to an interviewee important to make the prioritization procedures effective.

Pandemic policy on use/ownership of patient data. Several interviewees pointed out that a strong “agreement for secondary use of data and biological samples” is needed for an effective and fair prioritization in the secondary use of patient data and biological samples (P25). To support this agreement a “regulation on data use and access” is one important aspect that should be clarified upfront in preparing for pandemics (P26).

Quote (interview 11): “Who owns the data? Am I giving away my data? Am I still considered enough there? So in an instant everybody gets the feeling: "I’m giving something away. Am I giving away my rights?"

Professionalization of clinical research. In elaborating strategies and success conditions for prioritization of clinical studies several interviewees pointed out that more “competence in clinical research” (P27) is needed in Germany. During the pandemic, sometimes people with insufficient training in study design and other clinical research related competencies organized and conducted clinical research.

Quote (interview 16): “Maybe that’s part of the problem, that people are now doing clinical research who haven’t really done clinical research in the past, and then the collaborations don’t work”

Moreover, interviewees pointed out that the need for “fair play among scientists” (P28) serve as a condition of success for collaborative and effective research that qualifies for prioritization.