he spread of COVID-19 and the resulting social activity restrictions have severely impacted drug development and threatened the continuity of clinical trials in the US. Japanese pharmaceutical companies that develop drugs in the US were affected by these unprecedented circumstances as severely as US companies.

Moreover, due to their relatively limited financial and human resources (compared to the US pharmaceutical giants), these Japanese companies were forced to be more cautious in their decisions to start, postpone, or suspend clinical trials. How did these expatriates of Japanese companies in the US handle this pandemic?

Background

The Project Planning & Management (PP&M) Forum was founded to promote dialogue and reflection on the promotion of drug development projects and to enhance world-class project management skills. Its NY (New York) Chapter consists of representatives of subsidiaries of Japanese pharmaceutical companies located on the US East Coast. The NY Chapter of the PP&M Forum conducted an urgent survey of its members in July 2020 to find out how Japanese project management expatriates managed their projects, encouraged rational decision-making, and documented their valuable management experience under this high state of alert. The group has 120 individual members from approximately 30 companies, 29 of which provided information through this survey.

Study Phases

Survey responses were divided into study phases. Companies were allowed to choose more than one response, so the total number of responses exceeds 100%.

What study phase were you conducting or preparing when the pandemic began?

What aspects of project management were significantly affected by the pandemic?

Survey results indicate that the project management aspects most significantly affected by the pandemic were timeline, stakeholder management (i.e., explanation and coordination of opinions with internal and external stakeholders), cost, and quality (including patient safety). These are consistent with what project managers do most to ensure their projects’ success when managing clinical trials.

These aspects of the impact of the pandemic as well as project management actions taken in response are explained in separate sections below.

Stakeholder Management

How was the decision to suspend or discontinue your study made?

Five of thirteen companies conducting phase 1 studies decided to suspend or discontinue them due to COVID-19. Four of these five indicated that their decision to discontinue the clinical trial was based on information gathered by and recommendations from the trial CRO; recommendations from CROs that owned their phase 1 sites seemed particularly important. The one remaining answer was based on the principal investigator’s opinion.

Sponsors seem to have made their decision after fully taking into account the situation at clinical trial sites – their major stakeholders. Most decisions to discontinue were made in response to the lockdown (four out of five cases). This lockdown had a significant impact on stakeholder management, including stakeholders at company headquarters in Japan. There is no detailed information on the studies that were not suspended, but since the impact of the pandemic varied even within the US, the studies that were not suspended might have been conducted in less affected areas.

Among the eleven companies conducting phase 2 or phase 3 studies, four responded that their clinical trials were suspended or discontinued. Two of these four answered that the entire study was immediately and fully discontinued; the other two discontinued the study sequentially, site by site. The decision to discontinue a study was made by the sponsor (two respondents), by consultation between the study site and CRO, and by IRB recommendation. Compared to single-center phase 1 studies, the percentage of multicenter studies discontinued or suspended was much lower, and the process of making discontinuation or suspension decisions was more varied. The pandemic’s impact was likely different in multicenter studies because of their variable geography (its impact varied from location to location, and therefore may have been different from center to center).

Quality and Safety Management

Were protocol changes made in response to the pandemic?

In the phase 1 studies, eleven out of thirteen respondents made changes to their protocol in response to the pandemic. The changes were mainly the addition of COVID-19 testing (five responses), and of COVID-19 positive patients to the patient exclusion criteria (three) in a prompt effort to eliminate COVID-19’s effect (through infected patients) on the study. Some respondents did not make any changes to the protocol itself, but gave direction in separate written manuals distributed to their studies.

Four of the eleven respondents engaged in phase 2 and phase 3 multicenter trials revised their protocols during the preparation stage. These included the addition of COVID-19 testing (two respondents) and COVID-19 positive patients to the exclusion criteria (two). Compared with single-center studies, there were fewer cases of protocol changes during study preparation. However, in multicenter studies, the impact of COVID-19 may have been limited due to regional differences, or there may have been cases in which the situation was observed longer in order to avoid any hasty action. Three respondents made protocol changes in a phase 2 or phase 3 study; all three made this change to ease criteria in case the patient could not come to the hospital, to reduce the risk of infection associated with that patient’s visit.

How did the sponsor respond when it was not possible to perform the planned study assessments?

There may have been cases when data could not be obtained as specified in the protocol due to restrictions on patient visits. Seven of the thirteen respondents conducting a phase 1 study responded that if a protocol-specified item could not be measured, it was recorded as a protocol deviation. Six out of eleven respondents engaged in ongoing phase 2 and phase 3 studies also recorded these as deviations.

FDA guidance recommended that sponsors consider the risk of COVID-19 infection in patients and consider alternative methods if visiting the study site presented a risk. FDA has also commented that, in situations where it is anticipated that data will not be collected as specified in the protocol, and the protocol cannot be revised to record the deviation, such information should be summarized in the clinical study report. Survey responses were generally in line with this guideline. As previously mentioned, some sponsors responded by revising the protocol, but by recording missing data as deviations before that revision, they were able to respond quickly to situational changes.

What infection prevention measures were taken during your study?

For phase 1 studies, five of the thirteen respondents had specified social distancing between patients, and four had provisions for wearing facemasks and sanitizing hands. Some respondents also reported avoiding a large number of patient visits on the same day. When the survey was conducted in July 2020, infection prevention measures such as social distancing and facemasks had not been well adopted by the general US public, but results show that infection prevention measures were actively taken in phase 1 studies, where patients were often gathered in one place. For phase 2 or 3 studies, six respondents took no infection prevention measures. It may have been difficult to take consistent measures in a study with multiple facilities across a wide area of the US due to differences in the spread of infection and the government response in each State.

What action was taken if COVID-19 infections occured during your study?

For phase 1, only two of the thirteen respondents reported that COVID-19 infection actually occurred in their patients. Two cases treated the COVID-19 infection as an adverse event (AE) and the patients continued to participate in the study. In phase 2 or 3 trials, four of the eleven respondents reported that COVID-19 infection occurred in their studies. Of these four, two sponsored discontinued and two continued the study after recording infections as an AE. (The two studies that continued were anticancer drug studies, which would have been difficult to suspend from an ethical standpoint.)

Did you implement remote assessment?

Only two of thirteen respondents engaged in phase 1 studies conducted remote evaluation using telephone or web tools as an alternative to ensure patient safety However, seven out of eleven respondents engaged in phase 2 or 3 studies conducted a remote assessment. Remote assessment may have been difficult to implement in phase 1 studies because these are basically inpatient studies that require a variety of measurements in a short, condensed timeframe. On the other hand, in phase 2 or 3 studies, measurement items varied from study to study, so there may have been an effort to introduce remote evaluation starting with examinations that could be conducted from the patient’s home. It is also possible that it would have been difficult to continue the phase 2 or 3 study without the introduction of remote evaluation.

Did you implement remote monitoring?

Monitoring was the phase 1 clinical trial activity most impacted by COVID-19. Six out of thirteen respondents conducted remote Source Data Verification (SDV) without visiting the study site. For phases 2 and 3, five respondents switched to remote SDV and two reported that SDV was interrupted, another indication that monitoring was severely affected. Even when site visit monitoring was not possible as planned, respondents tried to maintain the study (and its quality) by quickly implementing remote monitoring during the pandemic’s unprecedented first wave.

Were investigational drugs delivered directly to study patients?

In the phase 2 and 3 studies, five out of eleven reported that they had switched (or were planning to switch) to delivering investigational drugs directly to the patient’s home. Increased infection risk due to a study site visit affected the study site’s study drug distribution. It is apparent that the respondents took prompt action to reduce this risk by sending investigational drugs directly to the patient’s home.

Summary of Actions Taken in Phase 1 and Phase 2/3 Studies

Table. Summary of sponsor responses to quality and safety questions.

Table. Summary of sponsor responses to quality and safety questions.

Timeline Management

In phase 2 or 3 studies, four out of eleven responded that patient enrollment was affected. Of these four, two answered that enrollment had almost stopped and the other two had dropped to about 50% of the pre-pandemic level. On the other hand, one responded that enrollment was relatively unaffected, and another reported that this aspect was generally difficult to analyze and discuss due to regional differences. Efforts tried to minimize the pandemic’s impact on study continuation; still, there were cases in which delays in patient enrollment affected the timeline.

Cost Management

In phase 1 studies, seven of thirteen respondents reported increased costs due to the pandemic. This increase included actual costs for COVID-19 testing and direct costs for CROs during the study interruption. In six of these seven cases, the sponsor paid these increased costs. In phase 2 or 3 trials, two respondents answered that cost increased during the study interruption period, and two answered that it did not increase. Although there were cases in which the study cost increased due to the pandemic, it appears that only the sponsor was responsible for the study cost.

Conclusions

For project managers dispatched to the US from pharmaceutical companies headquartered in Japan, it is important to accurately share the current pandemic situation and impact in the US with all their stakeholders, including Japanese management, in managing their clinical trials. Since the impact of COVID-19 was much less severe in Japan in 2020, this information from project managers in the US has important implications for making study continuity and improvement decisions for their US East Coast operations.