Head, Clinical Operations, Raptim Research

Dr. Chirag Shah

The COVID-19 pandemic has forced the clinical trials industry to accept and accelerate the use of digital health technologies to alleviate disruptions and mitigate risks caused by the spread of the virus. As we are aware, more than 75 pharma and biotech companies faced significant disruption in their clinical trials during that time.

Further, approximately 67% of disrupted clinical trials were due to the suspension of enrollment, followed by the delayed start of planned trials at 18.4% and slow enrollment at 14.4%.

 Within the 14.4% of trials affected by slow enrollment, more than 20% of these were due to the lack of availability of sites and investigators.

There were numerous clinical trials in progress during pandemic and the first and foremost challenge was the safety of trial participants. Sponsors/CRO needed to make study decisions about continuing trial recruitment, continued use of the investigational product, collection and management and processing of biological samples, and reporting of serious adverse events (SAEs) in such dire circumstances.

Based on our experience, the following outlines what processes and solutions Raptim Research implemented to mitigate the risk of COVID and conduct our studies per study timelines.

A detailed manual was prepared, which contained full contingency plans with the following case scenarios: if the participant turns COVID-19 positive; if the site staff turns COVID-19 positive; and if the site turns into the COVID hospital. The manual was submitted to both the Independent Ethics Committees (IEC) and Drugs Controller General of India (DCGI) in parallel.

To minimize or eliminate immediate hazards or to protect the life and well-being of research participants and limit exposure to COVID-19 infection, amendments to the protocols were developed following evolving FDA guidelines. It was implemented at the site prior to approval from IEC to eliminate immediate risk of COVID exposure. IEC and regulatory were then submitted with the amended protocol for approvals.

Participant visit was limited to the hospital. Visits where investigational product (IP) was supposed to be dispensed to the participant, then a possibility of delivering the IP to the participant’s residence was explored to minimize exposure. Participants were encouraged to contact the investigator over a video call in case it was required. In the event of rescheduling of visits, it was undertaken as a precautionary measure for COVID-19, these protocol deviations were not considered as violation unless they were found to be impacting participant's safety.

Raptim was involved in oncology study where pharmacokinetic samples of patients were being collected as part of the primary objective of the study. Participants were provided pick up and drop-off transportation at a sanitized and safe conveyance facility.

A secure system was implemented to upload source data, and remote verification was implemented to avoid on-site monitoring visits and thus would not impediment the review process. Backup CRCs (clinical research coordinators) and CRC for entry of data into the CRF were kept as a separate team to avoid delay. The monitoring plan was amended to accommodate remote monitoring visits. IEC were notified of this change and source was verified remotely via "21 CFR" compliant secured platform created by Raptim.

Based on the FDA guidelines, we have implemented following options to facilitate remote monitoring access to clinical site records:

If the site can provide appropriate resources and technical capabilities, consider establishing a secure remote viewing portal that would permit site staff to provide access to the site’s study documentation and/or trial participants’ source documents for the study monitor’s review.

Sites could upload certified copies of source records on an electronic system that contains appropriate security controls. The monitor could access the documents remotely for the purpose of source data verification.

The IEC played a major role during the pandemic to approve changes in the process and protocol amendments, as well as conducted online meetings to accelerate the procedures and provide expedited approvals.

New sites in tier two cities were initiated, which were not in red zone as per the existing guidelines at that time. Non-recruiting sites, which were under the red zones, were closed and new sites were initiated after conducting a remote qualification visit, which was properly documented.

In a single day, up to five participants maximum were scheduled for randomization, keeping the COVID protocol in background to minimize site staff visits and exposure. Follow up visits were synchronized as well. Site staff visits to hospitals, however, were eliminated to maintain safety.

If any questionnaires were to be completed by the principal investigators after physical examinations, that was done via video calling. Here the participant was observed through video calling, and the time of call and questions asked were documented in the source.

Medical monitors assessed the impact of COVID-19 on patient safety and IP dosing compliance and formulated mitigation strategies with project managers and with sponsors medical and operational teams, with the following outlines.

Precautionary measure for COVID-19 for all participants

Precautionary steps education, including social distancing, use of mask, hand washing, avoid gathering, and no touching nose, eyes, face

Use of medical facility if any COVID-related symptoms developed

History taking for COVID19 and general physical examination to rule out signs and symptoms of COVID-19

Separate record maintained of screening procedure for COVID-19 and safety measures taken for COVID-19. COVID screening checklist was created for assessment at each visit

If participant does not have any history related to contact with COVID participant and/or no signs/symptoms, it was considered as normal and no further testing was required. Re-emphasis of precautionary measures

If the test for COVID-19 was mandatory per protocol, the test was conducted for each participant at the time of screening or enrollment

Unless and until symptoms develop, testing for COVID-19 was not allowed for any participant as per the government regulation, and testing was only done as per government modalities

If suspicious of positive COVID-19, the participant was discontinued or dropped from the trial. However, during this time we did not find any suspicious patients.

Screening for signs and symptoms at the time of virtual visit by asking question related to COVID-19 disease. If apprehensive regarding COVID-19, immediate testing was performed and the respective authority was informed 

Suspended or minimized the scheduled in-person visit to avoid contamination from COVID-19. Virtual interim visits were implemented and only in-person screening, study-end visit and emergency visit for AE/SAE if possible and feasible

If participant was infected with COVID-19, but was asymptomatic, they were told to self isolate. If symptomatic, they were admitted in hospital.

Raptim Research was conducting a study for FDA submission in a dermatology indication during the pandemic with sample size of more than 900 patients. The plan was to screen around 1,000 patients to find eligible be and be enrolled. Out of the total randomized participants, 98.04% have completed the study and only 1.96% were withdrawn. Due to continuous patient retention strategy, only three participants were lost to follow up, while 15 participants withdrew consent.

The pandemic impacted the initial plan of recruitment. To cope with challenges, the following steps were implemented:

Initially, the study was planned with 10 sites; later 20-23 sites were approached to conduct the study

Ethics committee submission was done at 20 sites to get maximum sites ready to conduct the study.

Green zones (zero confirmed cases of COVID-19 in the last 21 days) as per the prevailing guidelines were initiated to conduct the study.

Initially, only half the IP was shipped to all sites to keep check on recruitment. Only the higher recruiting sites were re-supplied IP.

To replace the low recruiting sites, the backup sites with good patient population were initiated.

Efforts, such as arranging transportation for visits and regular follow up, were made to retain the enrolled patients and continue until the end of study.

During this time, the discontinuation of one participant was the only choice when they tested positive for COVID-19, as the dermatology trial could not continue because of a 15-day abstinence from treatment, creating a non-compliance of treatment situation

Successful studies conducted during a pandemic require collaboration, transparency and agility, along with a deep understanding of clinical research. With the right knowledge and experience, leveraging strategic partnerships can help to manage and execute clinical operations, even amid the most uncertain times.

The use of electronic tools and technology needs to be elaborated on by the Indian regulatory authority for conducting of clinical trials in pandemic. Solutions to conduct oncology/unmet medical need studies in the country need to be more technology driven. IECs needs to be empowered by the regulatory authority to make appropriate decisions considering the extent of pandemic in their area/city. Raptim Research has implemented tools and technology in order to finish the study with optimum quality and as per the timelines. The blend of human resources and the appropriate use of technology is essential to ride the wave of challenges in conducting clinical trials in the current, and potentially future, pandemic era.

 is a Project Manager, Clinical Trials; and 

 is a Head, Clinical Operations both forRaptim Research,Mumbai,India

https://www.biocentury.com/article/304745/a-biocentury-bio-joint-survey-finds-covid-19-has-forced-many-companies-to-modify-their-clinical-trials

https://endpts.com/covid-19-has-roiled-clinical-trial-plans-around-the-world-raising-concerns-over-the-industrys-future-on-new-drug-approvals/

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