Cindy Dukes

Cyntha Dukes, PA-C, MT

Vice President, Drug Development Services, Vaccines, Infectious Disease

Operational best practices

In response to the urgent need for a vaccine and treatment for COVID-19, researchers are, at this writing, running nearly 500 clinical trials (and counting) on a number of antivirals and vaccines.1

Vaccine trials for respiratory viruses, even in the best of circumstances, present a number of operational challenges for researchers, many of which are exacerbated in the face of a pandemic created by a novel virus.

A compressed timeline with no room for error

Although COVID-19 has yet proven to be a seasonal disease, it will likely recycle with other respiratory pathogens in the winter respiratory season. With that said, Phase I and II studies can be executed any time, although off-season is typically preferred so as to not confound the data with natural disease acquisition. Phase III randomised, controlled efficacy studies of vaccines aimed at preventing laboratory-confirmed disease are typically executed with the season in mind and make for an intense time for sponsors, contract research organisations (CROs) and sites. They must contend with an aggressive calendar that compresses study start and recruitment, the need for active surveillance of thousands of patients, complex supply and site logistics, high volumes of data, and alternatives to on-site monitoring. 

Geography and subject population

COVID-19 vaccine studies can be conducted anywhere in the world and can be designed around low or high incidence areas. Because regulatory agencies are prioritising COVID studies and giving approvals in record time, the geographies available for study are much more extensive than in the typical influenza or RSV study. Some countries or areas are yet to see spread of disease, and consideration should be given to including sites with or without current disease spread. Furthermore, thought should be given to whether subjects should be seronegative, which would also drive this decision. There are arguments that could be made for including both seronegative and seropositive subjects.

Planning

With respect to respiratory pandemic vaccine studies, the timeline is extraordinarily compressed, with potentially serious consequences for any delay or lack of attention to detail. The study must be the first priority for the team, and researchers and sponsors must consider new approaches for routine activities. The critical steps in the start-up process are to:

  • Stabilise the protocol as quickly as possible. It is difficult to prepare an extensive study plan if the protocol is still in flux.
  • Select the hemisphere and countries where the trial will run. These decisions will be based in part on answers to such questions as: Should subjects be seronegative or not?  What type of volunteers should be considered, general population,  older vs younger, healthcare workers etc.
  • Develop the monitoring plan, along with any monitoring oversight plan.  For pandemic vaccines, standard on-site visits may not be possible. Risk-based monitoring and options for remote visits and the use of video and data analytics should be considered.
  • Develop the investigator budget. Given the number of subjects typically involved, the budget will be substantial and may include additional needs or challenges for the investigative site.
  • Address contingencies in the manufacturing plan. With new vaccines in a pandemic situation, manufacturing will be tricky as the first lots don’t always pass the quality control/quality assurance process, delaying study start. Communicating the status transparently is critical so that all parties can make adjustments and be prepared for study start as soon as the vaccine can be shipped.
  • Ensure the availability of equipment. To handle vaccines and lab specimens, sites must have centrifuges and refrigerators/freezers, and of course, personal protection equipment.
  • Develop and stress test all systems. In the case of a pandemic vaccine, timelines for setting up and testing study systems such as eDiaries, EDC, interactive response technology (IRT), and electronic trial master files (eTMF) will be compressed significantly, and thus careful and thorough User Acceptance Tests (UATs) will be of utmost importance.
  • Develop the data management plan and statistical analysis plan (SAP). Plans for data management and data cleaning as well as plans for interim and final data analysis should be set prior to the FSI.

Enrollment

All sites within a hemisphere should begin competitive enrollment on or around the same day. With a pandemic study, overall competitive enrollment with no caps should be considered as depending on disease spread, site capabilities, and changing needs, some sites may suddenly be unable to participate.

Adverse event reporting

General, adverse events (AEs) or medically-intended AEs are usually captured for 28 days post vaccination, while serious adverse events (SAEs) and new onset chronic conditions (NOCDs) are reported for the duration of the trial. For a COVID study, an eDiary may not be suited to collecting reactogenicity (solicited events) due to the setup time requires, thus paper diaries may be required.

Monitoring and study documentation

COVID-19 studies amidst an outbreak require new approaches to monitoring beyond the standard remote and on-site visits. This might include data analytics, remote monitoring using technology to conduct visits to verify facilities, inspect vaccine storage/handling as well as source data verification.

Data management

Data will be coming in very, very rapidly, and it is essential to clean it continuously, rather than letting it wait until just before the study closes. The same is true for serology data, viral swabs results, and the reconciliation of SAEs.

COVID-19 clinical operations

Keeping your clinical trial on track in an evolving environment. 

Successful factors for COVID-19 studies

Respiratory vaccine studies are fast-paced from beginning to end, and pandemic studies move at lightning speed. In our experience, the keys to success include:

  • Flexibility and thinking out of the box.
  • Performing more activities in parallel in a shorter timeframe.
  • Careful planning, effective communication, and close collaboration between the sponsor, the CRO, the sites, and other vendors.
  • The ability to make decisions and resolve issues rapidly. Response time to questions and needs must be as short as possible. Within the same day is ideal.
  • Making the study the top priority within the organisation with internal advocates and leadership support.
  • Selecting investigative sites that are experienced in vaccine studies and have proven capabilities.
  • Taking extraordinary steps to ensure the availability of the study vaccine and any comparator.
  • Aggressively addressing any unanticipated delays.
  • Using a robust system for tracking progress and gathering data.
  • Designing monitoring plans to adapt to the various and changing sites’ needs.
  • Considering out-of-the-box solutions to ensure rapid execution while maintaining high quality performance and documentation.

The scope and timeframes of pandemic studies such as COVID19-studies leave no room for error and have a very steep learning curve with limited leeway to learn on the job. As the world awaits a vaccine for COVID-19, Sponsors must respond with a comprehensive, coordinated approach that accounts for contingencies, properly manages risk, holds to a firm schedule and applies best practices developed through years of experience. 

Reference

1 ClinicalTrials.gov.

MIT Technology Review article

Cindy Dukes provided commentary in a 26 May MIT Technology Review article:
Here’s what we have to do to show a coronavirus vaccine works